Tricyclic-2-pyridone compounds useful as HIV reverse transcriptase inhibitors

ABSTRACT

The present invention relates to tricyclic 2-pyridone compounds of formula (I):  
                 
 
     or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

FIELD OF THE INVENTION

[0001] This invention relates generally to tricyclic pyridone compoundswhich are useful as inhibitors of HIV reverse transcriptase,pharmaceutical compositions and diagnostic kits comprising the same,methods of using the same for treating viral infection or as assaystandards or reagents, and intermediates and processes for making suchtricyclic compounds.

BACKGROUND OF THE INVENTION

[0002] Two distinct retroviruses, human immunodeficiency virus (HIV)type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to theimmunosuppressive disease, acquired immunodeficiency syndrome (AIDS).HIV seropositive individuals are initially asymptomatic but typicallydevelop AIDS related complex (ARC) followed by AIDS. Affectedindividuals exhibit severe immunosuppression which predisposes them todebilitating and ultimately fatal opportunistic infections.

[0003] The disease AIDS is the consequence of HIV-1 or HIV-2 virusfollowing its complex viral life cycle. The virion life cycle involvesthe virion attaching itself to the host human T-4 lymphocyte immune cellthrough the binding of a glycoprotein on the surface of the virion'sprotective coat with the CD4 glycoprotein on the lymphocyte cell. Onceattached, the virion sheds its glycoprotein coat, penetrates into themembrane of the host cell, and uncoats its RNA. The virion enzyme,reverse transcriptase, directs the process of transcribing the RNA intosingle-stranded DNA. The viral RNA is degraded and a second DNA strandis created. The now double-stranded DNA is integrated into the humancell's genes and those genes are used for virus reproduction.

[0004] RNA polymerase transcribes the integrated viral DNA into viralmRNA. The viral RNA is translated into the precursor gag-pol fusionpolyprotein. The polyprotein is then cleaved by the HIV protease enzymeto yield the mature viral proteins. Thus, HIV protease is responsiblefor regulating a cascade of cleavage events that lead to the virusparticle's maturing into a virus that is capable of full infectivity.

[0005] The typical human immune system response, killing the invadingvirion, is taxed because the virus infects and kills the immune system'sT cells. In addition, viral reverse transcriptase, the enzyme used inmaking a new virion particle, is not very specific, and causestranscription mistakes that result in continually changed glycoproteinson the surface of the viral protective coat. This lack of specificitydecreases the immune system's effectiveness because antibodiesspecifically produced against one glycoprotein may be useless againstanother, hence reducing the number of antibodies available to fight thevirus. The virus continues to reproduce while the immune response systemcontinues to weaken. In most cases, without therapeutic intervention,HIV causes the host's immune system to be debilitated, allowingopportunistic infections to set in. Without the administration ofantiviral agents, immunomodulators, or both, death may result.

[0006] There are at least three critical points in the HIV life cyclewhich have been identified as possible targets for antiviral drugs: (1)the initial attachment of the virion to the T-4 lymphocyte or macrophagesite, (2) the transcription of viral RNA to viral DNA (reversetranscriptase, RT), and (3) the processing of gag-pol protein by HIVprotease.

[0007] Inhibition of the virus at the second critical point, the viralRNA to viral DNA transcription process, has provided a number of thecurrent therapies used in treating AIDS. This transcription must occurfor the virion to reproduce because the virion's genes are encoded inRNA and the host cell transcribes only DNA. By introducing drugs thatblock the reverse transcriptase from completing the formation of viralDNA, HIV-1 replication can be stopped.

[0008] A number of compounds that interfere with viral replication havebeen developed to treat AIDS. For example, nucleoside analogs, such as3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxythymidinene (d4T), 2′,3′-dideoxyinosine (ddI), and2′,3′-dideoxy-3′-thia-cytidine (3TC) have been shown to be relativelyeffective in certain cases in halting HIV replication at the reversetranscriptase (RT) stage.

[0009] An active area of research is in the discovery of non-nucleosideHIV reverse transcriptase inhibitors (NNRTIs). As an example, it hasbeen found that certain benzoxazinones and quinazolinones are active inthe inhibition of HIV reverse transcriptase, the prevention or treatmentof infection by HIV and the treatment of AIDS.

[0010] U.S. Pat. No. 5,874,430 describes benzoxazinone non-nucleosidereverse transcriptase inhibitors for the treatment of HIV. U.S. Pat. No.5,519,021 describe non-nucleoside reverse transcriptase inhibitors whichare benzoxazinones of the formula:

[0011] wherein X is a halogen, Z may be O.

[0012] EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptaseinhibitors which are quinazolinones of the formula (A):

[0013] wherein G is a variety of groups, R³ and R⁴ may be H, Z may be O,R² may be unsubstituted alkyl, unsubstituted alkenyl, unsubstitutedalkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, andoptionally substituted aryl, and R¹ may be a variety of groups includingsubstituted alkyl.

[0014] WO 95/12583 also describes HIV reverse transcriptase inhibitorsof formula A. In this publication, G is a variety of groups, R³ and R⁴may be H, Z may be O, R² is substituted alkenyl or substituted alkynyl,and R¹ is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273illustrates the asymmetric synthesis of one of the compounds of WO95/12583,

[0015] (S)-(-)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethynyl)-2(1H)-quinazolinone.

[0016] Synthetic procedures for making quinazolinones like thosedescribed above are detailed in the following references: Houpis et al.,Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al., J. Med. Chem. 1994,37, 2437-2444; and, Huffman et al., J. Org. Chem. 1995, 60, 1590-1594.

[0017] DE 4,320,347 illustrates quinazolinones of the formula:

[0018] wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring.Compounds of this sort are not considered to be part of the presentinvention.

[0019] Even with the current success of reverse transcriptaseinhibitors, it has been found that HIV patients can become resistant toa given inhibitor. Thus, there is an important need to developadditional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

[0020] Accordingly, one object of the present invention is to providenovel reverse transcriptase inhibitors.

[0021] It is another object of the present invention to provide a novelmethod for treating HIV infection which comprises administering to ahost in need of such treatment a therapeutically effective amount of atleast one of the compounds of the present invention, including apharmaceutically acceptable salt form thereof.

[0022] It is another object of the present invention to provide a novelmethod for treating HIV infection which comprises administering to ahost in need thereof a therapeutically effective combination of (a) oneof the compounds of the present invention and (b) one or more compoundsselected from the group consisting of HIV reverse transcriptaseinhibitors and HIV protease inhibitors.

[0023] It is another object of the present invention to providepharmaceutical compositions with reverse transcriptase inhibitingactivity comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form thereof.

[0024] It is another object of the present invention to provide noveltricyclic 2-pyridone compounds for use in therapy.

[0025] It is another object of the present invention to provide the useof novel tricyclic 2-pyridone compounds for the manufacture of amedicament for the treatment of HIV infection.

[0026] These and other objects, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of formula (I):

[0027] wherein R¹, R², R⁸, A, W, X, Y, and Z are defined below,including any stereoisomeric form, mixtures of stereoisomeric forms,complexes, prodrug forms or pharmaceutically acceptable salt formsthereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0028] [1] Thus, in an embodiment, the present invention provides anovel compound of formula (I):

[0029] or a stereoisomeric form or mixture of stereoisomeric forms or apharmaceutically acceptable salt form thereof, wherein:

[0030] A is a ring selected from:

[0031] P is O or S;

[0032] R^(b), at each occurrence, is independently selected from H, F,Cl, Br, I, CN, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₁₋₄ alkyl-O-, orC₁₋₄ alkyl-NH-, NH₂;

[0033] R^(c), at each occurrence, is independently selected from H, C₁₋₄alkyl, C₁₋₄ alkenyl, and C₁₋₄ alkynyl;

[0034] W is N or CR³;

[0035] X is N or CR^(3a);

[0036] Y is N or CR^(3b);

[0037] Z is N or CR^(3c);

[0038] provided that if two of W, X, Y, and Z are N, then the remainingare other than N;

[0039] R¹ is selected from the group C₁₋₄ alkyl substituted with 0-9halogen, cyclopropyl, hydroxymethyl, and CN;

[0040] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₆ alkyl substituted with 0-2 R⁴, C₂₋₆haloalkyl, C₂₋₅ alkenylsubstituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆cycloalkyl substituted with 0-2 R^(3d), phenyl substituted with 0-2R^(3d), and 3-6 membered heterocyclic system containing 1-3 heteroatomsselected from the group O, N, and S, substituted with 0-2 R^(3d);

[0041] R³ is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy,OCF₃, CF₃, F, Cl, Br, I, —(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—(CH₂)_(t)NHC(O)R⁷, —(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —S—C₁₋₄alkyl,—S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S;

[0042] R^(3a) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, CF₃, F, Cl, Br, I, —(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN,—C(O)R⁶, —(CH₂)_(t)NHC(O)R⁷, —(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰,—S—C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6membered heteroaromatic ring containing 1-4 heteroatoms selected fromthe group O, N, and S;

[0043] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0044] R^(3b) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0045] alternatively, R^(3a) and R^(3b) together form —OCH₂O —;

[0046] R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC (O)R⁷,—NHC (O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a);

[0047] alternatively, R^(3b) and R^(3c) together form —OCH₂O —;

[0048] R^(3d), at each occurrence, is independently selected from thegroup H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a),—NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and—SO₂NR⁵R^(5a);

[0049] R^(3e), at each occurrence, is independently selected from thegroup H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a),—NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and—SO₂NR⁵R^(5a);

[0050] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, OCF₃, —O(CO)—R¹³,—OS(O)₂C₁₋₄alkyl, —NR¹²R^(12a), —C(O)R¹³, —NHC(O)R¹³, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, —NHSO₂R¹⁰, and —SO₂NR¹²R^(12a);

[0051] R⁴ is selected from the group H, F, Cl, Br, I, C₁₋₆ alkylsubstituted with 0-2 R^(3e), C₃₋₁₀ carbocycle substituted with 0-2R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-10 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-2 R^(3e);

[0052] R⁵ and R^(5a) are independently selected from the group H andC₁₋₄ alkyl;

[0053] alternatively, R⁵ and R^(5a), together with the nitrogen to whichthey are attached, combine to form a 5-6 membered ring containing 0-1 Oor N atoms;

[0054] R⁶ is selected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, andNR⁵R^(5a);

[0055] R⁷ is selected from the group H, C₁₋₃ alkyl and C₁₋₃ alkoxy;

[0056] R⁸ is selected from the group H, (C₁₋₆ alkyl)carbonyl, C₁₋₆alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)oxycarbonyl,(C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄ alkyl)carbonyloxy(C₁₄ alkoxy)carbonyl,C₆₋₁₀ arylcarbonyloxy(C₁₋₄ alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆alkyl)carbonyl;

[0057] R⁹ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, C14 alkynyl,(C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy,(C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄ alkyl)carbonyloxy(C₁₋₄ alkoxy) carbonyl, C₆₋₁₀ arylcarbonyloxy (C₁₋₄ alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, phenyl (C₁₋₄alkoxy) carbonyl, and NR⁵R^(5a)(C₁₋₆ alkyl)carbonyl;

[0058] R¹⁰ is selected from the group C₁₋₄ alkyl and phenyl;

[0059] R¹¹ is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylsubstituted with C₃₋₆cycloalkyl substituted with 0-2 R^(3e), C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocycle substituted with 0-2 R^(3e);

[0060] R¹² and R^(12a) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkyl substituted with C₃₋₆cycloalkyl substituted with 0-2 R^(3e),and C₃₋₆ carbocycle substituted with 0-2 R^(3e);

[0061] alternatively, R¹² and R^(12a) can join to form 4-7 memberedheterocyclic ring;

[0062] R¹³ is selected from the group H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —O—C₂₋₆ alkenyl, —O—C₂₋₆alkynyl, NR¹²R^(12a), C₃₋₆carbocycle, and —O—C₃₋₆carbocycle; and

[0063] t is selected from 0 and 1.

[0064] [2] In a preferred embodiment, the present invention providescompounds of formula (I), wherein:

[0065] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₅ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(3d), and phenyl substituted with 0-2 R^(3d), and 3-6membered heterocyclic system containing 1-3 heteroatoms selected fromthe group O, N, and S, substituted with 0-2 R^(3d), wherein theheterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl,4-isoxazolyl, 2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and1,3-dioxanyl;

[0066] R³ and R^(3a), at each occurrence, are independently selectedfrom the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a),NO₂, —CN, C(O)R⁶, NHC(O)R⁷, NHC(O)NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S;

[0067] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0068] R^(3b) and R^(3c), at each occurrence, are independently selectedfrom the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a),NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O) NR⁵R^(5a);

[0069] alternatively, R^(3a) and R^(3b) together form —OCH₂O—;

[0070] R⁴ is selected from the group H, Cl, F, C₁₋₄ alkyl substitutedwith 0-2 R^(3e), C₃₋₆ carbocycle substituted with 0-2 R^(3e), phenylsubstituted with 0-5 R^(3e), and a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-2 R^(3e);

[0071] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0072] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a); and

[0073] R⁷ is selected from the group CH₃, C₂H₅, CH(CH₃)₂, OCH₃, OC₂H₅,and OCH(CH₃)₂.

[0074] [3] In another preferred embodiment, the present inventionprovides compounds of formula (I), wherein:

[0075] P is O;

[0076] Ring A is:

[0077] R^(b), at each occurrence, is selected from H, F, Cl, and Br,C₁₋₄ alkyl, CN, C₁₋₄ alkyl-NH-, NH₂;

[0078] R^(c) is selected from H and methyl;

[0079] W is CR³;

[0080] X is CR^(3a);

[0081] Y is CR^(3b);

[0082] Z is CR^(3c);

[0083] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₃ alkyl substituted with 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2R⁴, C₂₋₃ alkynyl substituted with 0-1 R⁴, and C₃₋₆ cycloalkylsubstituted with 0-2 R^(3d);

[0084] R³, R^(3a), R^(3b), and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F,Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC (O)NR⁵R^(5a);

[0085] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0086] R^(3e), at each occurrence, is independently selected from thegroup H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, —NR⁵R^(5a), —C(O)R⁶,and —SO₂NR⁵R^(5a);

[0087] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, , —O(CO)—R¹³, —SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, and —NR¹²R^(12a);

[0088] R⁴ is selected from the group H, Cl, F, C₁₋₄ alkyl substitutedwith 0-1 R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenylsubstituted with 0-2 R^(3e), and a 5-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-1 R^(3e), wherein the heterocyclic system is selectedfrom 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl,pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl;

[0089] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0090] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a);

[0091] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅;

[0092] R⁸ is H;

[0093] R⁹ is H, methyl, ethyl, propyl, and i-propyl;

[0094] R¹¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl, and C₃₋₆ carbocycle substituted with 0-2 R^(3e)wherein the C₃₋₆ carbocycle is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and phenyl; and

[0095] R¹² and R^(12a) are independently selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocyclesubstituted with 0-2 R^(3e) wherein the C₃₋₆ carbocycle is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl.

[0096] [4] In another preferred embodiment, the present inventionprovides compounds of formula (I), wherein:

[0097] R² is selected from the group methyl substituted with 0-3 R^(3f),C₁₋₃ alkyl substituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴,and C₂₋₃ alkynyl substituted with 1 R⁴;

[0098] R³, R^(3a), R^(3b), and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F,Cl, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O)NR⁵R^(5a);

[0099] alternatively, R³ and R^(3a) together form —OCH₂O—;

[0100] R^(3e), at each occurrence, is independently selected from thegroup CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a);

[0101] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, —OH, CN, —O—R¹¹, —O(CO)—R¹³, and—NR¹²R^(12a), —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, and —OS(O)₂methyl;

[0102] R⁴ is selected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropylsubstituted with 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1R^(3e), cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with0-2 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl;

[0103] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0104] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a);

[0105] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and

[0106] R⁹ is selected from H and methyl.

[0107] [5] In another preferred embodiment, the present inventionprovides compounds of formula (I), wherein:

[0108] R² is selected from the group methyl substituted with 0-2 R^(3f),methyl substituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-2 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴, 2-propynylsubstituted with 0-2 R⁴, and cyclopropyl substituted with 0-1 R^(3d);

[0109] R^(3e), at each occurrence, is independently selected from thegroup CH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a);

[0110] R⁴ is selected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropylsubstituted with 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1R^(3e), cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with0-2 R³e, and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl ;

[0111] R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅;

[0112] R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, andNR⁵R^(5a);

[0113] R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅;

[0114] R⁸ is H.

[0115] [6] In another preferred embodiment, the present inventionprovides compounds of formula (I), wherein:

[0116] R¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,cyclopropyl, CF₃, CF₂CH₃, CN, and hydroxymethyl;

[0117] R² is selected from the group methyl substituted with 0-2 R^(3f),methyl substituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-1 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴;

[0118] R³, R^(3b), and R^(3c) are H;

[0119] R^(3e) is CH₃;

[0120] R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —NR¹²R^(12a);

[0121] R⁴ is selected from the group H, cyclopropyl substituted with 0-1R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl;

[0122] R¹² and R^(12a) are independently selected from H, methyl, ethyl,propyl, and i-propyl, and C₃₋₆ carbocycle substituted with 0-2 R^(3e)wherein the C₃₋₆ carbocycle is selected from cyclopropyl.

[0123] [7] Preferred compounds of the present invention are thosecompounds wherein the compound is of formula (Ic):

[0124] [8] Preferred compounds of the present invention includecompounds of formula (I) wherein the compound of formula (I) is selectedfrom the compounds shown in Table 1.

[0125]7-fluoro-2-methyl-5-[(6-methyl-2-pyridinyl)methyl]-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0126]5-(2-cyclopropylethynyl)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0127] 7-fluoro-5-propyl-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0128] 5-butyl-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0129] 7-fluoro-5-(4-fluorophenylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;

[0130]7-fluoro-5-(2-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0131] 7-fluoro-5-(isopropyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0132]7-fluoro-5-(3-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0133]7-fluoro-5-(4-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0134] 7-fluoro-5-(3-propynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0135]7-fluoro-5-(2-pyridylethynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0136]7-fluoro-5-(2-(2-pyridyl)ethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0137] 3-chloro-7-fluoro-5-propyl-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0138] 7-fluoro-5-(3-propenyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0139]5-(2-cyclopropylethyl)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0140] 7-fluoro-5-(ethynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0141] 7-fluoro-5-(2-ethoxyethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0142] 5-Butyl-7-chloro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0143] 7-Chloro-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0144]7-Chloro-5-(2-cyclopropylethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0145] 7-Chloro-5-cyclopropylethynyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0146]7-Chloro-5-(N-cyclopropylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0147] 7-Chloro-5-hydroxymethyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0148]7-Chloro-3-methyl-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0149]7-Chloro-5-(2-cyclopropylethyl)-3-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0150] 7-Chloro-5-(n-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0151] 7-Chloro-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0152] 7-Chloro-5-(2-methoxyethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0153]7-Chloro-5-(i-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0154]7-Chloro-5-(N-methyl-N-i-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0155]7-Chloro-5-(cyclopropylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0156]7-Chloro-5-(n-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0157]7-Chloro-5-(cyclobutylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0158]7-Chloro-5-(i-butylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0159] 7-Chloro-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0160] 7-Cyano-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0161] 7-Cyano-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0162]7-Chloro-5-(cyclopropylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0163]7-Chloro-5-(cyclopropanesulfinylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0164]7-Chloro-5-(t-butylsulfinylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0165]7-Chloro-5-(methylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0166]7-Chloro-5-(ethylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0167]7-Chloro-5-(i-propylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0168]7-Fluoro-5-(i-propylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0169]7-Chloro-5-(t-butylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0170]7-Chloro-5-(cyclopropylmethoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0171]7-Chloro-5-(cyclobutoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0172]5-(Cyclobutoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0173]5-(Cyclopropylmethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0174]7-Chloro-3-methyl-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0175] 7-Chloro-3-methyl-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0176] 7-Cyano-3-methyl-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0177]7-Chloro-2-methyl-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0178] 3,7-Dichloro-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0179] 4,7-Dichloro-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0180] 7-Chloro-5-(ethoxyethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0181] 7-Chloro-5-(n-butyl)-5-methyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0182] 7-Chloro-5-(i-propoxymethyl)-5-methyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0183] 7-Chloro-5-(n-butyl)-5-cyano-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0184] 7-Chloro-5-(n-butyl)-5-(hydroxymethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0185] 7-Chloro-5-(n-butyl)-5-difluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0186] 7-Chloro-5-(i-propoxymethyl)-5-difluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0187] 5-(n-Butyl)-5-(1,1-difluoroethyl)-7-Fluoro-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0188] 7-Chloro-5-(n-butyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0189] 7-Cyano-5-(n-butyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0190] 7-Chloro-5-(ethoxymethyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0191] 5-(allyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0192]5-(2-methyl-1-propenyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0193] 5-(1-propynyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0194] 5-(cyanomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0195]5-(2-(ethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0196]5-(2-(dimethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0197]5-(2-(methylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0198] 5-(2-ethoxyethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0199]5-(2-(i-propylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0200]5-(2-(diethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0201]5-(2-(cyclopropylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0202] 5-(pentyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0203] 5-(i-butyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0204] 5-(vinyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0205] 5-(imidazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0206] 5-(pyrazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0207]5-(1,2,4-triazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0208]5-(i-propylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0209] 5-(i-propoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0210]5-(2-(methylethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0211]5-(2-(i-propylethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0212]5-(2-(pyrrolidinyl)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0213] 5-(2-(methoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0214] 5-(i-propoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0215]5-(3-pentanylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0216] 5-(dimethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0217]5-(i-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0218]5-(cyclopropylmethylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0219] 5-(allylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0220]5-((R)-sec-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0221]5-((S)-sec-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0222] 5-(diethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0223] 3-chloro-5-(propyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0224] 5-(butyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0225]5-(2-(i-propoxy)ethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0226]5-(i-propylaminomethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0227]5-(i-propoxymethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0228]5-(2-ethoxyethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0229]5-(sec-butylaminomethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0230]5-(cyclopentylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0231]5-(cyclobutylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0232]5-(dimethylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0233]5-(pyrrolidinylmethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0234]5-(cyclopropylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0235]5-(2-(dimethoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0236]5-(2-(diethoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

[0237]5-(2-(1,3-dioxolanyl)methyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one; and

[0238] 5-(2-(methoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one.

[0239] The present invention also provides a novel pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt form thereof

[0240] The compositions and methods of use comprising the compounds ofthe present invention include compositions and methods of use comprisingthe compounds of the present invention and stereoisomeric forms thereof,mixtures of stereoisomeric forms thereof, complexes thereof, crystallineforms thereof, prodrug forms thereof and pharmaceutically acceptablesalt forms thereof

[0241] In another embodiment, the present invention provides a novelmethod for treating HIV infection which comprises administering to ahost in need of such treatment a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt formthereof

[0242] In another embodiment, the present invention provides a novelmethod of treating HIV infection which comprises administering, incombination, to a host in need thereof a therapeutically effectiveamount of:

[0243] (a) a compound of formula (I); and

[0244] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors and HIV protease inhibitors.

[0245] In another embodiment, the present invention provides a novelmethod of treating HIV infection which comprises administering, incombination, to a host in need thereof a therapeutically effectiveamount of:

[0246] (a) a compound of formula (I); and

[0247] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors, HIV protease inhibitors, CCR-5inhibitors, and fusion inhibitors.

[0248] Preferred reverse transcriptase inhibitors useful in the abovemethod of treating HIV infection are selected from the group AZT, ddC,ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893,trovirdine, MKC-442, HBY 097, HBY1293, GW867, ACT, UC-781, UC-782,RD4-2025, MEN 10979, AG1549 (S1153), TMC-120, TMC-125, Calanolide A, andPMPA. Preferred protease inhibitors useful in the above method oftreating HIV infection are selected from the group saquinavir,ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623,GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, VX-175, MK-944,and VX-478, the CCR-5 inhibitor is selected from TAK-779 (Takeda),SC-351125 (SCH-C, Schering) and SCH-D (Schering), and the fusioninhibitor is selected from T-20 amd T1249.

[0249] In an even more preferred embodiment, the reverse transcriptaseinhibitor is selected from the group AZT, efavirenz, and 3TC and theprotease inhibitor is selected from the group saquinavir, ritonavir,nelfinavir, and indinavir.

[0250] In a still further preferred embodiment, the reversetranscriptase inhibitor is AZT.

[0251] In another still further preferred embodiment, the proteaseinhibitor is indinavir.

[0252] In another embodiment, the present invention provides apharmaceutical kit useful for the treatment of HIV infection, whichcomprises a therapeutically effective amount of:

[0253] (a) a compound of formula (I); and,

[0254] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors and HIV protease inhibitors, in oneor more sterile containers.

[0255] In another embodiment, the present invention provides noveltricyclic 2-pyridone compounds for use in therapy.

[0256] In another embodiment, the present invention provides the use ofnovel tricyclic 2-pyridone compounds for the manufacture of a medicamentfor the treatment of HIV infection.

[0257] In another embodiment, the present invention provides that Ring Ais

[0258] In another embodiment, the present invention provides that Ring Ais

[0259] In another embodiment, the present invention provides that R¹ isCF₃, CF₂CH₃, and CHF₂.

[0260] In another embodiment, the present invention provides that R¹ isselected from the group CF₃, C₂F₅, CF₂CH₃, CHF₂, CH₂F and cyclopropyl.

[0261] In another embodiment, the present invention provides that R¹ ismethyl, ethyl, propyl, i-propyl and butyl.

[0262] In another embodiment, the present invention provides that R¹ isCN and hydroxymethyl.

[0263] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₅ alkylsubstituted with 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2R^(3d), and phenyl substituted with 0-2 R^(3d), and 3-6 memberedheterocyclic system containing 1-3 heteroatoms selected from the group0, N, and S, substituted with 0-2 R^(3d), wherein the heterocyclicsystem is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl,3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl,2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.

[0264] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₃ alkylsubstituted with 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2 R⁴, C₂₋₃alkynyl substituted with 0-1 R⁴, and C₃₋₆ cycloalkyl substituted with0-2 R^(3d).

[0265] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₃ alkylsubstituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴, and C₂₋₃alkynyl substituted with 1 R⁴.

[0266] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-2 R^(3f), methylsubstituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-2 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴, 2-propynylsubstituted with 0-2 R⁴, and cyclopropyl substituted with 0-1 R^(3d).

[0267] In another embodiment, the present invention provides that R² isselected from the group methyl substituted with 0-2 R^(3f), methylsubstituted with 0-2 R⁴, ethyl substituted with 0-2 R⁴, propylsubstituted with 0-1 R⁴, ethenyl substituted with 0-2 R⁴, 1-propenylsubstituted with 0-2 R⁴, 2-propenyl substituted with 0-2 R⁴, ethynylsubstituted with 0-2 R⁴, 1-propynyl substituted with 0-2 R⁴.

[0268] In another embodiment, R² is selected from the group methylsubstituted with 0-2 R³f, methyl substituted with 0-2 R⁴, and ethylsubstituted with 0-2 R⁴.

[0269] In another embodiment, R² is R^(2c).

[0270] In another embodiment, the present invention provides thatR^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, , —O(CO)—R¹³, —SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, and —NR¹²R^(12a).

[0271] In another embodiment, the present invention provides thatR^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, C₁₋₄ alkyl, —OH, CN, —O—R¹¹, —O(CO)—R¹³, and —NR¹²R^(12a),—SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, and —OS(O)₂methyl.

[0272] In another embodiment, the present invention provides that R³f,at each occurrence, is independently selected from the group H, F, Cl,Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, and—NR¹²R^(12a).

[0273] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, C₁₋₄ alkyl substituted with 0-2R^(3e), C₃₋₆ carbocycle substituted with 0-2 R^(3e), phenyl substitutedwith 0-5 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-2R^(3e).

[0274] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, C₁₋₄ alkyl substituted with 0-1R^(3e), C₃₋₅ carbocycle substituted with 0-2 R^(3e), phenyl substitutedwith 0-2 R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl.

[0275] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropyl substitutedwith 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1 R^(3e),cyclobutyl substituted with 0-1 R³e, phenyl substituted with 0-2 R^(3e),and a 5-6 membered heterocyclic system containing 1-3 heteroatomsselected from the group O, N, and S, substituted with 0-1 R^(3e),wherein the heterocyclic system is selected from the group 2-pyridyl,3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl.

[0276] In another embodiment, the present invention provides that R⁴ isselected from the group H, Cl, F, CH₃, CH₂CH₃, cyclopropyl substitutedwith 0-1 R^(3e), 1-methyl-cyclopropyl substituted with 0-1 R^(3e),cyclobutyl substituted with 0-1 R^(3e), phenyl substituted with 0-2R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-1R^(3e), wherein the heterocyclic system is selected from the group2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl, triazolyl,1,3-dioxolanyl, and 1,3-dioxanyl.

[0277] In another embodiment, the present invention provides that R⁸ isH.

[0278] In another embodiment, the present invention provides that R⁹ isH, methyl, ethyl, propyl, and i-propyl.

[0279] The invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention also encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment to describe additional even more preferred embodiments of thepresent invention. Furthermore, any elements of an embodiment are meantto be combined with any and all other elements from any of theembodiments to describe additional embodiments.

DEFINITIONS

[0280] It will be appreciated that the compounds of the presentinvention contain an asymmetrically substituted carbon atom, and may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated. All tautomers of shown ordescribed compounds are also considered to be part of the presentinvention.

[0281] As used herein, the term “tricyclic 2-pyridones” is intended toinclude the compounds 5,10-Dihydro-2H-benzo[b][1,7]naphthyridin-1-onewhich are represented by the compounds of Formula I.

[0282] The processes of the present invention are contemplated to bepracticed on at least a multigram scale, kilogram scale, multikilogramscale, or industrial scale. Multigram scale, as used herein, ispreferably the scale wherein at least one starting material is presentin 10 grams or more, more preferably at least 50 grams or more, evenmore preferably at least 100 grams or more. Multikilogram scale, as usedherein, is intended to mean the scale wherein more than one kilogram ofat least one starting material is used. Industrial scale as used hereinis intended to mean a scale which is other than a laboratory scale andwhich is sufficient to supply product sufficient for either clinicaltests or distribution to consumers.

[0283] The present invention is intended to include all isotopes ofatoms occurring on the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0284] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering.

[0285] When any variable (e.g., Rb) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁴, then saidgroup may optionally be substituted with up to two R⁴ groups and R⁴ ateach occurrence is selected independently from the definition of R⁴.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

[0286] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0287] As used herein, the following terms and expressions have theindicated meanings.

[0288] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. By way of illustration, the term“C₁₋₁₀ alkyl” or “C₁-C₁₀ alkyl” is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. “C₁₋₄ alkyl” is intended toinclude C₁, C₂, C₃, and C₄ alkyl groups. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example -C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).Examples of haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” is intended to include hydrocarbon chains of either astraight or branched configuration and one or more unsaturatedcarbon-carbon bonds which may occur in any stable point along the chain,such as ethenyl, propenyl and the like. C₂₋₁₀ alkenyl, is intended toinclude C₂, C₃, C₄, C₅, C_(6,) C₇, C₈, C₉, and C₁₀ alkenyl groups.“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more triple carbon-carbon bondswhich may occur in any stable point along the chain, such as ethynyl,propynyl and the like. C₂₋₁₀ alkynyl, is intended to include C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkynyl groups.

[0289] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo. “Counterion” is used to represent a small, negativelycharged species such as chloride, bromide, hydroxide, acetate, sulfateand the like.

[0290] As used herein, “aryl” or “aromatic residue” is intended to meanan aromatic moiety containing the specified number of carbon atoms, suchas phenyl or naphthyl. As used herein, “carbocycle” or “carbocyclicresidue” is intended to mean any stable 3, 4, 5, 6, or 7-memberedmonocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl.

[0291] As used herein, the term “heterocycle” or “heterocyclic system”is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicor 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturatedpartially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized. Anoxo group may be a substituent on a nitrogen heteroatom to form anN-oxide. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. It is preferred that the total number of S and O atoms in theheterocycle is not more than 1. As used herein, the term “aromaticheterocyclic system” is intended to mean a stable 5, 6, or 7-memberedmonocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclicaromatic ring which consists of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, O andS. It is preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 1.

[0292] Examples of heterocycles include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 1,3-dioxolanyl, 1,3-dioxanyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

[0293] As used herein, “HIV reverse transcriptase inhibitor” is intendedto refer to both nucleoside and non-nucleoside inhibitors of HIV reversetranscriptase (RT). Examples of nucleoside RT inhibitors include, butare not limited to, AZT, ddC, ddI, d4T, PMPA, and 3TC. Examples ofnon-nucleoside RT inhibitors include, but are no limited to, delavirdine(Pharmacia and Upjohn U90152S), efavirenz (DuPont), nevirapine(Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly), MKC-442(Triangle), HBY 097 (Hoechst), HBY1293 (Hoechst), GW867 (GlaxoWellcome), ACT (Korean Research Institute), UC-781 (Rega Institute),UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), MEN 10979 (MenariniFarmaceutici) AG1549 (S1153; Agouron), TMC-120, TMC-125, and CalanolideA.

[0294] As used herein, “HIV protease inhibitor” is intended to refer tocompounds that inhibit HIV protease. Examples include, but are notlimited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538),indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome),nelfinavir (Agouron, AG-1343), palinavir (Boehringer Ingelheim),BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413(Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical),CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (ParkeDavis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690(Pharmacia and Upjohn), tipranavir (Pharmacia and Upjohn, U-140690),DMP-450 (DuPont), AG-1776, VX-175, MK-944, VX-478 and ABT-378.Additional examples include the cyclic protease inhibitors disclosed inWO93/07128, WO 94/19329, WO 94/22840, and PCT Application NumberUS96/03426.

[0295] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like.

[0296] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0297] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication commensurate with a reasonable benefit/risk ratio.

[0298] Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.Examples of prodrugs at R⁸ and at R⁹ are C₁₋₆ alkylcarbonyl, C₁₋₆alkoxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl.

[0299] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. Only stable compounds are contemplated bythe present invention.

[0300] “Substituted” is intended to indicate that one or more hydrogenson the atom indicated in the expression using “substituted” is replacedwith a selection from the indicated group(s), provided that theindicated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto(i.e., ═O) group, then 2 hydrogens on the atom are replaced.

[0301] “Therapeutically effective amount” is intended to include anamount of a compound of the present invention alone or an amount of thecombination of compounds claimed or an amount of a compound of thepresent invention in combination with other active ingredients effectiveto inhibit HIV infection or treat the symptoms of HIV infection in ahost. The combination of compounds is preferably a synergisticcombination. Synergy, as described for example by Chou and Talalay, Adv.Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case,inhibition of HIV replication) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at suboptimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedantiviral effect, or some other beneficial effect of the combinationcompared with the individual components.

[0302] As used herein, “treating” or “treatment” cover the treatment ofa disease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

[0303] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

SYNTHESIS

[0304] The compounds of Formula I can be prepared using the reactionsand techniques described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

[0305] Scheme 1 illustrates a method of preparing keto-anilines from anappropriately substituted 2-aminobenzoic acid (wherein R represents R³,R^(3a), R^(3b), and R^(3c)). The acid is converted to itsN-methoxy-N-methyl amide derivative which can then be displaced toobtain the R¹-substituted ketone. The keto-anilines are usefulintermediates for the presently claimed compounds.

[0306] Scheme 2 describes another method of preparing keto-anilines,this time from an appropriately substituted aniline. After iodinationand amine protection, a group such as trifluoromethyl can be introducedusing a strong base and ethyl trifluoroacetate. Deprotection providesthe keto-aniline. Additional means of preparing keto-anilines are knownto one of skill in the art, e.g, Houpis et al, Tetr. Lett. 1994, 35(37),6811-6814, the contents of which are hereby incorporated herein byreference.

[0307] Another method of making 2-trifluoroacetylanilines is shown inScheme 3. After forming the protected aniline, the amide is then reducedand the trifluoromethyl group added. Oxidation with an oxidant, such asMnO₂, provides the useful intermediate.

[0308] Scheme 4 describes a method of converting the protected anilineto the tricyclic structure. Metallation of the chloropyridine with LDAfollowed by condensation with the trifluoromethylketone gave thetertiary alcohol. Cyclization to the azaacridone was accomplished byheating in DMF with K2C03 for base. After protection with SEM-Cl, theacridone was condensed with CF3TMS and Bu4NF to give the fully aromatictricycle. Addition of nucloephiles such as cyanide and organometallicsgenerated the quaternary addition products. Conversion of themethoxypyridine to the pyridone products was accomplished by heatingwith HCl or HBr.

[0309] While the above schemes describe methods of preparing the benzoanalogs (i.e. wherein W, X, Y, and Z are all carbon), they can bemodified by one skilled in the art to prepare the heterocyclic varietieswherein W, X, Y, or Z are equal to nitrogen.

[0310] Scheme 5 illustrates specific steps for forming the aminoketoneIIIc. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃CF₂, andCF₃CF₂CF₂) is useful for making some of the presently claimed compounds.Pg is an amine protecting group as defined previously, preferably trityl(triphenylmethyl). The protected or unprotected aminobenzaldehyde,preferably protected, is treated with a perfluoralkyl trimethylsilane,preferably trifluoromethyl trimethylsilane, followed by fluoride anion,preferably tetrabutylammonium fluoride. In the same fashion, CF₃CF₂TMS,CF₃CF₂CF₂TMS can also be used to prepare the appropriately substitutedketones. Other sources of fluoride anion such as sodium fluoride,potassium fluoride, lithium fluoride, cesium fluoride as well asoxyanionic species such as potassium tert-butoxide, sodium methoxide,sodium ethoxide and sodium trimethylsilanolate can also be used..Aprotic solvents such as DMF and THF can be used, preferably THF. Theamount of perfluoralkyl trimethylsilane used can be from about 1 toabout 3 equivalents with an equivalent amount of fluoride anion oroxyanionic species. The reaction can be typically carried out attemperatures between about −20° C. to about 50° C., preferably about −10to about 10° C., more preferably about 0° C.

[0311] Conversion of IIIb to IIIc can be achieved by using an oxidizingagent well known to one of skill in the art such as MnO₂, PDC, PCC,K₂Cr₂O₇, CrO₃, KMnO₄, BaMNO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant isMnO2. Such conversion can be performed in an aprotic solvent like THF,DMF, dichloromethane dichloroethane, or tetrachloroethane, preferablydichloromethane.

[0312] In addition to the methods of obtaining keto-anilines describedin Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can alsobe used as shown in Scheme 6. This reaction is accomplished by using ananionic nucleophile of the group R^(1a). See Mack et al, J. HeterocyclicChem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6),825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38;Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959,24, 1214-1219.

[0313] It is preferred that the stoichiometry of the isatoic anhydridereagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or2.0) of anion (or anion precursor) is preferred to force the conversionand improve the isolated yield. Preferably, the temperature used is from−20 to +35° C., with temperatures below 0° C. being more preferred and−20° C. being even more preferred. Reactions are run to about completionwith time dependent upon inter alia nucleophile, solvent, andtemperature. Preferably this nucleophilic addition is run in THF, butany aprotic solvent would be suitable. Reaction with the activenucleophilic anion is the only criterion for exclusion of a solvent.

[0314] Patent Publications WO98/14436, WO98/45276, and WO01/29037describe other methods of preparing the appropriately substitutedanilines and are hereby incorporated by reference.

[0315] The keto-anilines can alsobe converted to the tricyclic compoundsusing procedures described in the examples.

[0316] One enantiomer of a compound of Formula I may display superioractivity compared with the other. Thus, both of the followingstereochemistries are considered to be a part of the present invention.

[0317] When required, separation of the racemic material can be achievedby HPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605.

[0318] Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES

[0319] Abbreviations used in the Examples are defined as follows: “°C.”for degrees Celsius, “d” for doublet, “dd” for doublet of doublets, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “H” for hydrogen orhydrogens, “hr” for hour or hours, “m” for multiplet, “M” for molar,“min” for minute or minutes, “MHz” for megahertz, “MS” for massspectroscopy, “nmr” or “NMR” for nuclear magnetic resonancespectroscopy, “t” for triplet, “TLC” for thin layer chromatography,“ACN” for acetic anhydride, “CDI” for carbonyl diimidazole, “DIEA” fordiisopropylethylamine, “DIPEA” for diisopropylethylamine, “DMAP” fordimethylaminopyridine, “DME” for dimethoxyethane, “EDAC” for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “LAH” forlithium aluminium hydride, “TBAF” for tetrabutylammonium fluoride,“TBS-Cl” for t-butyldimethylsilyl chloride, and “TEA” for triethylamine.

[0320] All reactions were run under a nitrogen atmosphere at roomtemperature and most were not optimized. The reactions were followed byTLC. Reactions run over night were done so for adequate time. Reagentswere used as received. Dimethylformamide, tetrahydrofuran andacetonitrile were dried over molecular sieves. All other solvents werereagent grade. Ethanol and methanol were absolute and water wasdeionized. Melting points were determined in open capillary tubes on aMel-Temp apparatus and are uncorrected. Column chromatographies weredone on flash silica gel. Exceptions to any of the conditions above arenoted in the text. Ciral HPLC separations were done using chiral columnswhich gave the enantiomers in >99% EE.

[0321] The following methods are illustrated in the synthethic schemesthat follow the methods. While the schemes are described for specificcompounds, the same methods were employed to synthesize the othercompounds that are listed in the table of examples.

Example 1

[0322] Compound VIII, wherein R=(6-Methylpyrid-2-Yl)Methyl

[0323] Step A: Preparation of compound II.

[0324] To a solution of amino ketone I (19.4 g, 281 mmol) indichloromethane (400 mL) at room temperature was added DIPEA (49 mL, 843mmol) followed by trityl bromide (30.3 g, 281 mmol) and the resultingreaction mixture was allowed to stir at room temperature for 15 minutes.The reaction mixture was poured onto 3N HCl and extracted withdichloromethane (4×200 mL). The combined dichloromethane extracts weredried over anhydrous Na₂SO₄ and concentrated in vacuo to provide 85 g ofcompound II, (126 g theoretical, 67%). ¹H NMR (300 MHz, CDCl₃) δ10.29(brs, 1H), 7.43(d, 1H, J=6 Hz), 7.3(m, 15H), 6.78(m, 1H), 6.29(m, 1H). ¹⁹FNMR (282 MHz, CDCl₃) δ−69.34(s, 3F), −128.28(s, 1F). Anal. (C₂₇H₁₉NOF₄)C, H, N.

[0325] Step B: Preparation of compound III.

[0326] To a solution of 2-methoxy-3-chloropyridine (11.9 g, 83.1 mmol)in THF (600 mL) at −78° C. was added a 2M solution of LDA in THF (45.6mL, 91.4 mmol) followed by compound II (37.35 g, 83.1 mmol), and theresulting reaction mixture was allowed to stir while warming to roomtemperature for 30 minutes. The reaction mixture was poured ontosaturated ammonium chloride and extracted with ethyl acetate (3×200 mL).The combined extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes eluant) provided 25.9g of compound III (74.1 g theoretical, 35%). ¹H NMR (300 MHz, CDCl₃)δ7.91(d, 1H, J=6 Hz), 7.4-6.9(m, 17H), 6.51(m, 1H), 6.08(m, 1H), 4.01(s, 3H). ¹⁶F NMR (282 MHz, CDCl₃) δ−76.81(br s, 3F), −128.36(s, 1F).Anal. (C₃₃H₂₅N₂O₂ClF₄) C, H, N.

[0327] Step C: Preparation of compound IV.

[0328] To a solution of compound III (25.89 g, 43.65 mmol) indichloromethane (225 mL) at room temperature was added TFA (225 mL) andthe resulting reaction mixture was allowed to stir at room temperaturefor one hour. The reaction mixture was poured onto saturated sodiumbicarbonate and extracted with ethyl acetate (3×200 mL). The combinedethyl acetate extracts were dried over anhydrous NaSO₄ and concentratedin vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 14.28g of the deprotected compound (15.31 g theoretical, 93%). ¹H NMR (300MHz, DMSO-d₆) δ8.10(d, 1H, J =6 Hz), 7.27(m, 1H), 6.9(m, 1H), 6.75(m,1H), 6.65(m, 1H), 3.99(s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−74.95(br s,3F), −122.01 (s, 1F) . Anal. (Cl₄H₁₁N₂O₂ClF₄) C, H, N.

[0329] To a solution of the above deprotected compound (2.0 g, 5.70mmol) in DMSO (40 mL) at room temperature was added cesium carbonate(9.29 g, 28.5 mmol) and the resulting reaction mixture was allowed tostir at 120° C. for 8 hours. The reaction mixture was poured onto 1N HCland the solids were filtered off. The residue was washed sequentiallywith water and ethanol and ether and dried in vacuo to provide 1.12 g ofcompound IV (1.39 g theoretical, 81 %). ¹H NMR (300 MHz, CDCl₃) δ11.88(br s, 1H), 8.10(m, 1H), 7.95(m, 1H), 7.85(m, 1H), 7.75(m, 1H), 7.60(m,1H). ¹⁹F NMR (282 MHz, CDCl₃) δ−119.46(s, 3F), −145.79(s, 1F). Anal.(C₁₃H₉N₂O₂F) C, H, N.

[0330] Step D: Preparation of compound V.

[0331] To a solution of compound IV (2.31 g, 9.45 mmol) in DMF (40 mL)at room temperature was added DIPEA (8.24 mL, 47.3 mmol) followed bySEMCl (3.35 mL, 18.9 mmol), and the resulting reaction mixture wasallowed to stir at room temperature overnight. The reaction mixture waspoured onto water and extracted with ethyl acetate (2×50 mL). Thecombined ethyl acetate extracts were dried over anhydrous NaSO₄ andconcentrated in vacuo. Chromatography (SiO₂, 20% acetone-hexanes eluant)provided 5.04 g of compound V (5.21 g theoretical, 96%). ¹H NMR (300MHz, CDCl₃) δ8.1-8.0(m, 2H), 7.9-7.8(m, 2H), 7.5-7.4(m, 1H), 5.83(s,2H), 4.15(s, 3H), 3.6 m, 2H), (1.0(m, 2H), 0.01(s, 9H). ¹⁹F NMR (282MHz, CDCl₃) δ−119.02(s, 1F). Anal. (Cl₉H₂₃N₂O₃SiF₄) C, H, N.

[0332] Step E: Preparation of compound VI.

[0333] To a solution of compound V (5.04 g, 13.46 mmol), in THF (60 mL)at room temperature was added CF₃TMS (6.0 mL, 40.4 mmol) followed byTBAF (4.04 mL, 4.04 mmol) and the resulting reaction mixture was allowedto stir at 0° C. for 30 minutes. The reaction mixture was poured ontowater and extracted with ethyl acetate (2×100 mL). The combined ethylacetate extracts were dried over anhydrous MgSO₄ and concentrated invacuo to give a brown oil which was used in the next step withoutfurther purification.

[0334] A solution of the above brown oil (crude product, 13.46 mmol) inTFA (70 mL) was allowed to stir at room temperature for 30 minutes. Thereaction mixture was concentrated in vacuo. The residue was taken up inTHF (70 mL), methanol (70 mL), and saturated sodium bicarbonate (70 mL),and the resulting reaction mixture was allowed to stir at roomtemperature for 5 minutes. The reaction mixture was poured onto waterand extracted with ethyl acetate (2×100 mL). The combined ethyl acetateextracts were dried over MgSO₄ and concentrated in vacuo. Chromatography(SiO₂, 20-30% EtOAc-hexanes eluant) provided 3.52 g of compound VI (3.99g theoretical, 93%). ¹H NMR (300 MHz, CDCl₃) δ8.6-8.5(m, 1H), 8.1-8.0(m,2H), 7.8-7.6(m, 1H), 4.32(s, 3H). ¹⁹F NMR (282 MHz, CDCl₃) δ−52.42(s,3F), −104.57(s, 1F). Anal. (C₁₄H₈N₂OF₄) C, H, N.

[0335] Step F: Preparation of compound VII(R=(6-methylpyrid-2-yl)methyl).

[0336] To a solution of lutidine (275 μl, 2.36 mmol) in THF (3 mL) at−78° C. was added a 2M solution of LDA in THF (1.18 mL, 2.36 mmol) andthe resulting reaction mixture was allowed to stir at −78° C. for 15minutes. Thereafter, compound VI (175 mg, 0.59 mmol) was added and theresulting reaction mixture was allowed to stir at −78° C. for 30minutes. The reaction mixture was poured onto saturated NH₄Cl andthereafter partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 30 mgof compound VIIa (238 g theoretical, 13%). ¹H NMR (300 MHz, CDCl₃)δ7.63(d, 1H, J=6 Hz), 7.3(m, 1H), 7.1-7.0(m, 2H), 6.95(s, 1H),6.8-6.6(m, 2H), 6.4(d, 1H, J=8 Hz), 4.03(s, 3H), 2.38 (s, 3H). ¹⁹F NMR(282 MHz, CDCl₃) δ−76.02(s, 3F), −122.84(s, 1F). Anal. (C₂₁Hl₇N₃OF₄) C,H, N.

[0337] Step G: Preparation of compound of formula VIII(R=(6-methylpyrid-2-yl)methyl).

[0338] To a solution of VII (R=(6-methylpyrid-2-yl)methyl) (30 mg, 0.074mmol) in ethanol (1 mL) was added a 48% aqueous solution of HBr (1 mL)and the resulting reaction mixture was allowed to stir at reflux for 1.5hours. The reaction mixture is poured onto saturated NaHCO₃ andextracted with ethyl acetate (3×25 mL). The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, EtOAc eluant) provided 23 mg of compound VIII(R=(6-methylpyrid-2-yl)methyl)(29 mg theoretical, 79%). ¹H NMR (300 MHz,acetone-d₆) δ8.15 (br s, 1H), 7.4(m, 1H), 7.35(m, 2H), 7.0-6.85(m, 2H),6.8-6.75(m, 1H), 6.5-6.6(m, 1H), 4.03(m, 2H), 2.23(s, 3H). ¹⁹F NMR (282MHz, acetone-d₆) δ−76.08(s, 3F), −124.98(s, 1F). Anal. (C₂₀Hl₅N₃O₁F₄) C,H, N.

[0339] Example 2

Compound VIII, wherein R=Cyclopropylacetylenyl

[0340]

[0341] Step F: Preparation of compound VII (R=cyclopropylacetylenyl).

[0342] To a solution of cyclopropylacetylene (167 μl, 1.52 mmol) in THF(2 mL) at 0° C. was added a 1.6M solution of nBuLi in THF (0.85 mL, 1.36mmol) and the resulting reaction mixture was allowed to stir at 0° C.for 20 minutes. Thereafter, the reaction mixture was cooled to −78° C.and compound VI (100 mg, 0.34 mmol) was added and the resulting reactionmixture was warmed to 0° C. and allowed to stir with warming to roomtemperature over a period of several hours. The reaction mixture wasquenched with saturated NH₄Cl and poured onto water and extracted withethyl acetate (2×25 mL). The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and dried in vacuo. Chromatography (SiO₂, 50%EtOAc-hexanes eluant) provided 30 mg of the title compound (238 gtheoretical, 13%). ¹H NMR (300 MHz, CDCl₃) δ7.8(d, 1H, J=6 Hz), 7.5(m,1H), 7.25(m, 1H), 7.1(m, 1H), 6.85-6.8(m, 1H), 6.75(br s, 1H), 4.06(s,3H), 1.48(s, 3H), 1.4(m, 1H), 0.9(m, 2H), 0.8(m, 2H). ¹⁹F NMR (282 MHz,CDCl₃) δ−77.30(s, 3F), −122.50(s, 1F). High resolution mass spec:calculated for C₁₉H₁₅N₂OF₄ (M+H) : 363.1121, found 363.1128.

[0343] Step G: Preparation of compound of formula VIII(R=cyclopropylacetylenyl).

[0344] To a solution of compound VII (R=cyclopropylacetylenyl)(18 mg,0.05 mmol) in dichloromethane (1 mL) at room temperature was added TMSI(100 μl of a 1M solution in dichloromethane, 0.01 mmol) and theresulting reaction mixture was allowed to stir at room temperatureovernight. The reaction mixture was poured onto water and extracted withethyl acetate (2×25 mL). The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂,20% EtOAc-hexanes eluant) provided 3 mg of the title compound (17 mgtheoretical, 18%). ¹H NMR (300 MHz, CDCl₃) δ7.5(m, 1H), 7.35(br s, 1H),7.05-7.0(m, 1H), 6.95-6.85 (m, 2H), 6.85-6.8(m, 1H),4.06(s, 3H), 1.57(s,3H), 1.4 (m, 1H), 0.9(m, 2H), 0.8(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃)δ−77.26(s, 3F), −121.64(s, 1F). High resolution mass spec: calculatedfor C₁₈H₁₃N₂OF₄ (M+H)⁺: 349.0964, found 349.0939.

Example 3 Compound VIII, wherein R=N-Propyl

[0345]

[0346] Step F: Preparation of compound of formula VII (R=n-propyl).

[0347] To a solution of VI (175 mg, 0.59 mmol) in THF (2 mL) at −78° C.was added a 2M solution of n-propyl magnesium chloride in ether (1.48mL, 2.95 mmol) and the resulting reaction mixture was allowed to stir at−78° C. for 15 minutes. The reaction mixture was quenched with saturatedNH₄Cl and poured onto water and extracted with ethyl acetate (2×50 mL).Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 144 mg ofcompound VIIc (201 g theoretical, 72%). ¹H NMR (300 MHz, CDCl₃) δ7.8(d,1H, J=6 Hz), 7.5(m, 1H), 7.25(m, 1H), 7.1(m, 1H), 6.85-6.8(m, 1H),6.75(br s, 1H), 4.06(s, 3H), 1.48(s, 3H), 1.4(m, 1H), 0.9(m, 2H), 0.8(m,2H). ¹⁹F NMR (282 MHz, CDCl₃) δ−76.15(s, 3F), −122.88(s, 1F). Highresolution mass spec: calculated for C₁₇H₁₇N₂OF₄ (M+H)⁺: 341.1277, found341.1282.

[0348] Step G: Preparation of compound of formula VIII (R=n-propyl).

[0349] To a solution of VII (R=n-propyl)(144 mg, 0.42 mmol) in ethanol(2 mL) at room temperature was added a 48% aqueous solution of HBr (2mL) and the resulting reaction mixture was allowed to stir at reflux for1.5 hours. The reaction mixture is poured onto saturated NaHCO₃ andextracted with ethyl acetate (3×25 mL). The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 84 mg of thetitle compound (137 mg theoretical, 61%). ¹H NMR (300 MHz, acetone-d₆)δ11.56 (br s, 1H), 8.74(br s, 1H), 7.44(m, 1H), 7.2(m, 1H), 7.05-6.95(m,2H), 6.42(m, 1H), 6.5-6.6(m, 1H), 4.03(m, 2H), 2.4(m, 2H), 1.05(m, 3H).¹⁹F NMR (282 MHz, acetone -d₆) δ−76.48(s, 3F), −124.44(s, 1F). Anal.(Cl₆H₁₄N₂OF₄) C, H, N.

Example 4 Compound VIII, wherein R=N-Butyl

[0350]

[0351] Step F: Preparation of compound of formula VII (R=n-butyl)

[0352] To a solution of VI (500 mg, 1.69 mmol) in THF (8 mL) at −78° C.was added a 2M solution of n-butyl magnesium chloride in ether (4.22 mL,8.44 mmol) and the resulting reaction mixture was allowed to stir at−78° C. for 15 minutes. The reaction mixture was quenched with saturatedNH₄Cl and poured onto water and extracted with ethyl acetate (2×50 mL).Chromatography (SiO₂, 10% EtOAc-hexanes eluant) provided 337 mg ofcompound VII (R=n-butyl)(599 mg theoretical, 56%). ¹H NMR (300 MHz,CDCl₃) δ7.70(d, 1H, J=6 Hz), 7.1(m, 1H), 7.0-6.95(m, 1H), 6.85(m, 1H),6.8(m, 1H), 6.7(br s, 1H), 4.06(s, 3H), 2.4(m, 2H), 1.35(m, 2H), 1.1 (m,2H), 0.8(t, 3H, J =7 Hz)), 0.8(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃) δ3176.12(s, 3F), −122.86(s, 1F). Anal. (C₁₈H₁₈N₂OF₄) C, H, N.

[0353] Step G: Preparation of compound of formula VIII (R=n-butyl).

[0354] To a solution of VII (R=n-butyl)(64 mg, 0.18 mmol) in ethanol (2mL) at room temperature was added a 48% aqueous solution of HBr (2 mL)and the resulting reaction mixture was allowed to stir at reflux for 1.5hours. The reaction mixture is poured onto saturated NaHCO₃ andextracted with ethyl acetate (3×25 mL). The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 36 mg of thetitle compound (61 mg theoretical, 59%). ¹H NMR (300 MHz, CDCl₃)δ12.5(br s, 1H), 7.55(br s, 1H), 7.1(m, 1H), 7.0-6.8(m, 3H), 6.35(m,1H), 2.3(m, 2H), 1.35 (m, 2H), 1.05(m, 2H), 0.8(t, 3H, J=7 Hz). ¹⁹F NMR(282 MHz, CDCl₃) δ−75.84(s, 3F), −122.14(s, 1F). Anal. (C₁₇Hl₆N₂OF₄) C,H, N.

Example 5 Compound VIII, wherein R=4-Fluorophenylmethyl

[0355]

[0356] Step F: Preparation of compound of formulaVII(R=4-fluorophenylmethyl).

[0357] To a solution of VI (196 mg, 0.66 mmol) in THF (2 mL) at −78° C.was added a 0.25M solution of p-fluorophenylmagnesium chloride in ether(13.2 mL, 3.3 mmol) and the resulting reaction mixture was allowed tostir at −78° C. for 45 minutes. The reaction mixture was quenched withsaturated NH₄Cl and poured onto water and extracted with ethyl acetate(2×50 mL). Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 153mg of compound VII (R=4-fluorophenylmethyl)(268 mg theoretical, 57%). ¹HNMR (300 MHz, CDCl₃) δ7.73(d, 1H, J=6 Hz), 7.3(m, 1H), 7.1(m, 1H),6.95(m, 1H), 6.8-6.6(m, 5H), 6.55(br s, 1H), 3.99(s, 3H), 3.7(m, 2H).¹⁹F NMR (282 MHz, CDCl₃) δ−74.25(s, 3F), −116.27(s, 1F), −122.53(s, 1F).Anal. (C₂₁H₁₅N₂OF₅) C, H, N.

[0358] Step G: Preparation of compound of formulaVIII(R=4-fluorophenylmethyl).

[0359] To a solution of VII (R=4-fluorophenylmethyl)(153 mg, 0.38 mmol)in ethanol (4 mL) at room temperature was added a 48% aqueous solutionof HBr (4 mL) and the resulting reaction mixture was allowed to stir atreflux for 1.5 hours. The reaction mixture is poured onto saturatedNaHCO₃ and extracted with ethyl acetate (3×25 mL). The combined ethylacetate extracts were dried over anhydrous MgSO₄ and concentrated invacuo. Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 89 mg ofthe title compound (149 mg theoretical, 60%). ¹H NMR (300 MHz, CDCl₃)δ12.0(br s, 1H), 7.3(m, 1H), 7.0(m, 1H), 6.9(m, 1H), 6.85-6.7(m, 5H),6.55(m, 1H). ¹⁹F NMR (282 MHz, CDCl₃) δ−73.89(s, 3F), −116.01(s, 1F),−121.68(s, IF). Anal. (C₂₀H₁₃N₂OF₅) C, H, N.

Example 6 Compound VIII, wherein R=2-Pyridylmethyl

[0360]

[0361] Step F: Preparation of compound of formula VII(R=2-pyridylmethyl).

[0362] To a solution of 2-picoline (134 μl, 1.36 mmol) in THF (2 mL) at−78° C. was added a 2M solution of LDA in THF (0.76 mL, 1.52 mmol) andthe resulting reaction mixture was allowed to stir at −78° C. for 15minutes. Thereafter, compound VI (100 mg, 0.34 mmol) was added and theresulting reaction mixture was allowed to stir at −78° C. for 30minutes. The reaction mixture was poured onto saturated NH₄Cl andthereafter partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 111mg of compound VII (R=2-pyridylmethyl)(132 mg theoretical, 84%). ¹H NMR(300 MHz, CDCl₃) δ8.3(d, 1H, J=5 Hz), 7.64(d, 1H, J=6 Hz), 7.3(m, 2H),7.1(m, 1H), 6.95(m, 1H), 6.8-6.6(m, 2H), 4.1(m, 2H), 4.02(s, 3H). ¹⁹FNMR (282 MHz, CDCl₃) δ−75.99(s, 3F), −122.57(s, 1F). Anal. (C₂₀H₁₅N₃OF₄)C, H, N.

[0363] Step G: Preparation of compound of formula VIII(R=2-pyridylmethyl).

[0364] To a solution of VII (R=2-pyridylmethyl)(111 mg, 0.28 mmol) inethanol (2 mL) was added a 48% aqueous solution of HBr (2 mL) and theresulting reaction mixture was allowed to stir at reflux for 1.5 hours.The reaction mixture is poured onto saturated NaHCO₃ and extracted withethyl acetate (3×25 mL). The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂,EtOAc eluant) provided 77 mg of the title compound (105 mg theoretical,73%). ¹H NMR (300 MHz, DMSO-d₆) δ11.7(br s, 1H), 9.0 (br s, 1H), 8.3(d,1H, J=4 Hz), 7.5(m, 1H), 7.45(m, 1H), 7.25(m, 1H), 7.05-6.95(m, 3H),6.8(d, 1H, J=7 Hz), 6.45(d, 1H, J =7 Hz), 4.0(m, 2H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−74.98(s, 3F), −123.69(s, 1F). Anal. (C₁₉H₁₃N₃OF₄) C, H, N.

Example 7 Compound VIII, wherein R=I-Propyl

[0365]

[0366] Step F: Preparation of compound of formula VII(R=i-propyl).

[0367] To a solution of VI (175 mg, 0.59 mmol) in THF (2 mL) at −78° C.was added a 2M solution of isopropyl magnesium chloride in ether (1.48mL, 2.95 mmol) and the resulting reaction mixture was allowed to stir at−78° C. for 15 minutes. The reaction mixture was quenched with saturatedNH₄Cl and poured onto water and extracted with ethyl acetate (2×50 mL).The combined ethyl acetate extracts were dried over anhydrous MgSO₄ andconcentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant)provided 144 mg of compound VII (R=i-propyl)(201 mg theoretical, 72%).¹H NMR (300 MHz, CDCl₃) δ7.6(d, 1H, J=6 Hz), 7.3(m, 1H), 7.05(m, 1H),6.95(m, 1H), 6.65(m, 1H), 4.04(s, 3H), 2.6(m, 1H), 1.05(m, 6H). ¹⁹F NMR(282 MHz, CDCl₃) δ−64.80(s, 3F), −122.85(s, 1F). High resolution massspec: calculated for C₁₇H₁₇N₂OF₄ (M+H)⁺: 341.1277, found 341.1276.

[0368] Step G: Preparation of compound of formula VIII(R=i-propyl).

[0369] To a solution of VII (R=i-propyl)(144 mg, 0.42 mmol) in ethanol(2 mL) at room temperature was added a 48% aqueous solution of HBr (2mL) and the resulting reaction mixture was allowed to stir at reflux for1.5 hours. The reaction mixture is poured onto saturated NaHCO₃ andextracted with ethyl acetate (3×25 mL). The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 63 mg of thetitle compound (137 mg theoretical, 46%). ¹H NMR (300 MHz, acetone-d₆)δ11.0 (br s, 1H), 8.3 (br s, 1H), 7.4-7.2(m, 2H), 7.1(m, 1H), 6.95(d,1H, J=7 Hz), 6.4(m, 1H), 2.7(m, 1H), 1.0(m, 6H). ¹⁹F NMR (282 MHz,acetone-d₆) δ−65.46(s, 3F), −124.43(s, 1F). Anal. (C₁₆H₁₄N₂OF₄) C, H, N.

Example 8 Compound VIII, wherein R=3-Pyridylmethyl

[0370]

[0371] Step F: Preparation of compound of formula VII (3-pyridylmethyl).

[0372] To a solution of 3-picoline (230 μl, 2.36 mmol) in THF (3 mL) at−78° C. was added a 2M solution of LDA in THF (1.33 mL, 2.66 mmol) andthe resulting reaction mixture was allowed to stir at −78° C. for 15minutes. Thereafter, compound VI (175 mg, 0.59 mmol) was added and theresulting reaction mixture was allowed to stir at −78° C. for 30minutes. The reaction mixture was poured onto saturated NH₄Cl andthereafter partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 8 mgof compound VII (3-pyridylmethyl)(230 mg theoretical, 3%). ¹H NMR (300MHz, CDCl₃) δ8.25(d, 1H, J=6 Hz), 8.1(m, 1H0, 7.69(d, 1H, J=6 Hz),7.3(m, 1H), 7.1(m, 2H), 6.9(m, 2H), 6.7(m, 1H), 6.55(br s, 1H), 4.01(s,3H), 3.75(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃) δ−74.42(s, 3F), −122.07(s,1F). High resolution mass spec: calculated for C₂₀H₁₆N₃OF₄ (M+H)⁺:390.1230, found 390.1248.

[0373] Step G: Preparation of compound of formula VIII(3-pyridylmethyl).

[0374] To a solution of VII (3-pyridylmethyl)(8 mg, 0.02 mmol) inethanol (1 mL) was added a 48% aqueous solution of HBr (1 mL) and theresulting reaction mixture was allowed to stir at reflux for 1.5 hours.The reaction mixture is poured onto saturated NaHCO₃ and extracted withethyl acetate (3×25 mL). The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 5%MeOH-dichloromethane eluant) provided 4 mg of the title compound (7.5 mgtheoretical, 53%). ¹H NMR (300 MHz, acetone-d₆) δ11.0(br s, 1H), 8.4 (brs, 1H), 8.2(m, 2H), 7.6(m, 1H), 7.4-7.2(m, 2H), 7.15-7.0(m, 3H), 6.65(m,1H), 3.95(m, 2H). ¹⁹F NMR (282 MHz, acetone-d₆) δ−74.81(s, 3F),−124.05(s, 1F). High resolution mass spec: calculated for C₁₉H₁₄N₃OF₄(M+H)⁺: 376.1073, found 376.1060.

Example 9 Compound VIII, wherein R=4-Pyridylmethyl

[0375]

[0376] Step F: Preparation of compound of formula VII(R=4-pyridylmethyl).

[0377] To a solution of 4-picoline (230μl, 2.36 mmol) in THF (3 mL) at−78° C. was added a 2M solution of LDA in THF (1.33 mL, 2.66 mmol) andthe resulting reaction mixture was allowed to stir at −78° C. for 15minutes. Thereafter, compound VI (175 mg, 0.59 mmol) was added and theresulting reaction mixture was allowed to stir at −78° C. for 30minutes. The reaction mixture was poured onto saturated NH₄Cl andthereafter partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 116mg of compound VII (R=4-pyridylmethyl)(230 g theoretical, 50%). ¹H NMR(300 MHz, CDCl₃) δ8.25(m, 1H), 7.68(d, 1H, J=6 Hz), 7.25(m, 1H),7.05-6.95(m, 2H), 6.8-6.65(m, 3H), 4.0(s, 3H), 3.75(m, 2H). ¹⁹F NMR (282MHz, CDCl₃) δ−74.83(s, 3F), −122.13(s, 1F). Anal. (C₂₀H₁₅N₃OF₄) C, H, N.

[0378] Step G: Preparation of compound of formula VIII(R=4-pyridylmethyl).

[0379] To a solution of VII (R=4-pyridylmethyl)(116 mg, 0.30 mmol) inethanol (2 mL) was added a 48% aqueous solution of HBr (2 mL) and theresulting reaction mixture was allowed to stir at reflux for 1.5 hours.The reaction mixture is poured onto saturated NaHCO₃ and extracted withethyl acetate (3×25 mL). The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂,EtOAc eluant) provided 93 mg of the title compound (113 mg theoretical,82%). ¹H NMR (300 MHz, acetone-d₆) δ10.65(br s, 1H), 8.2 (m, 3H), 7.5(m,1H), 7.3 (m, 1H) , 7.1-6.9 (m, 4H), 6.6 (m, 1H), 3.95 (m, 2H) . ¹⁹F NMR(282 MHz, acetone-d₆) δ−75.45(s, 3F), −124.13(s, 1F). Anal.(C₁₉H₁₃N₃OF₄) C, H, N.

Example 10 Compound VIII, wherein R=3-Propynyl

[0380]

[0381] Step F: Preparation of compound of formula VII (R=3-propynyl).

[0382] To a solution of 1-TMS-1-propyne (300 μl, 2.02 mmol) in THF (3mL) at −78° C. was added a 2M solution of LDA in THF (1.14 mL, 2.28mmol) and the resulting reaction mixture was allowed to stir at −78° C.for 20 minutes. Thereafter, compound VI (150 mg, 0.51 mmol) was addedand the resulting reaction mixture was allowed to stir at −78° C. 30minutes. The reaction mixture was poured onto saturated NH₄Cl andthereafter partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 102mg of compound VII (R=3-propynyl)(207 mg theoretical, 49%). ¹H NMR (300MHz, CDCl₃) δ7.72(d, 1H, J=6 Hz), 7.2(m, 1H), 7.0(m, 1H), 6.9(m, 1H),6.8(m, 1H), 6.75(br s, 1H), 4.07(s, 3H), 3.35(m, 2H). ¹⁹F NMR (282 MHz,CDCl₃) δ−75.68(s, 3F), −123.05(s, 1F). High resolution mass spec:calculated for C₂₀H₂₁N₂OSiF₄ (M+H)⁺: 409.1359, found 409.11365.

[0383] Step G: Preparation of compound of formula VIII (R=3-propynyl).

[0384] To a solution of compound VII (R=3-propynyl)(102 mg, 0.25 mmol)in dichloromethane (5 mL) at room temperature was added TMSI (2 ml of a1M solution in dichloromethane, 2 mmol) and the resulting reactionmixture was allowed to stir at room temperature for 4 hours. Thereaction mixture was poured onto water and extracted withdichloromethane (2×25 mL). The combined dichloromethane extracts weredried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography(SiO₂, 20% EtOAc-hexanes eluant) provided 66 mg of the trimethylsilylprotected compound (99 mg theoretical, 67%). ¹H NMR (300 MHz, CDCl₃)δ12.4(br s, 1H), 7.5(br s, 1H), 7.15(m, 1H), 7.05(m, 1H), 7.0-6.85 (m,2H), 6.4(d, 1H, J =7 Hz), 3.3(m, 2H), 0.05(s, 9H). ¹⁹F NMR (282 MHz,CDCl₃) δ−75.37 (s, 3F), −122.19(s, 1F) . Anal. (C₁₉H₁₈N₂OSiF₄) C, H, N.

[0385] To a solution of the above trimethylsilyl protected compound (66mg, 0.17 mmol) in methanol (1 mL) at room temperature was addedpotassium carbonate (117 mg, 0.85 mmol) and the resulting reactionmixture was allowed to stir for one hour. The reaction mixture waspoured onto water and extracted with ethyl acetate (2×50 mL). Thecombined ethyl acetate extracts were dried over anhydrous MgSO₄ and invacuo. Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 34 mg ofthe title compound (55 mg theoretical, 82%). ¹H NMR (300 MHz, CDCl₃)δ12.4(br s, 1H), 7.6(br s, 1H), 7.2(m, 1H), 7.05(m, 1H), 7.0-6.9(m, 2H),6.4(d, 1H, J =7 Hz), 3.3(m, 2H), 1.8(m, 1H). ¹⁹F NMR (282 MHz, CDCl₃)δ−76.19 (s, 3F), -121.68(s, 1F). Anal. (C₁₆H₁₀N₂OF₄) C, H, N.

Example 11 Compound VIII, wherein R=2-Pyridylethynyl

[0386]

[0387] Step F: Preparation of compound of formula VII(R=2-pyridylethynyl).

[0388] To a solution of 2-ethynylpyridine (157 μl, 1.52 mmol) in THF(1.5 mL) at −78° C. was added a 1.6M solution of nBuLi in THF (0.85 mL,1.36 mmol) and the resulting reaction mixture was allowed to stir at−78° C. for 15 minutes. Thereafter, compound VI (175 mg, 0.59 mmol) wasadded and the resulting reaction mixture was allowed to stir withwarming to room temperature for 30 minutes. The reaction mixture waspoured onto saturated NH₄Cl and thereafter partitioned between ethylacetate and 0.1N HCl. The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂,50% EtOAc-hexanes eluant) provided 39 mg of compound VII(R=2-pyridylethynyl)(136 mg theoretical, 29%). ¹H NMR (300 MHz, CDCl₃)δ8.65(m, 1H), 7.8-7.7(m, 2H), 7.65-7.55(m, 2H), 7.4-7.25(m, 2H), 7.1(m,1H), 6.9(m, 1H), 6.85(br s, 1H), 4.08(s, 3H). ¹⁹F NMR (282 MHz, CDCl₃)δ−76.62(s, 3F), −121.98(s, 1F). Anal. (C₂₁H₁₃N₃OF₄) C, H, N.

[0389] Step G: Preparation of compound of formula VIII(R=2-pyridylethynyl).

[0390] To a solution of compound VII (R=2-pyridylethynyl)(26 mg, 0.065mmol) in dichloromethane (2.5 mL) at room temperature was added TMSI (1ml of a 1M solution in dichloromethane, 0.01 mmol) and the resultingreaction mixture was allowed to stir at room temperature overnight. Thereaction mixture was poured onto water and extracted with ethyl acetate(2×25 mL). The combined ethyl acetate extracts were dried over anhydrousMgSO₄ and concentrated in vacuo. Chromatography (SiO₂, EtOAc eluant)provided 9 mg of the title compound (25 mg theoretical, 36%). ¹H NMR(300 MHz, acetone-d₆) δ11.45(br s, 1H), 8.6 (m, 1H), 7.95(m, 1H),7.75(m, 1H), 7.6-7.4(m, 3H), 7.25(m, 1H), 7.12(d, 1H, J=7 Hz), 6.67(d,1H, J=7 Hz). ¹⁹F NMR (282 MHz, acetone-d₆) δ−77. 54(s, 3F), −123.67(s,1F). Anal. (C₂₀H₁₁N₃OF₄) C, H, N.

Example 12 Compound VIII, wherein R=2-(2-Pyridyl)Ethyl

[0391]

[0392] Step A: Preparation of compound VII (R=2-pyridylethynyl).

[0393] To a solution of VII (R=2-pyridylethynyl)(20 mg, 0.05 mmol) inethanol (1 mL) at room temperature was added ammonium formate (20 mg)and 5% Pd/C (20 mg) and the resulting reaction mixture was allowed tostir at reflux for 1.5 hours. The reaction mixture was filtered throughCelite and the filterate concentrated in vacuo. Chromatography (SiO₂,40% EtOAc-hexanes eluant) provided 15 mg of compound VII(R=2-pyridylethyl)(20 mg theoretical, 75%). ¹H NMR (300 MHz, CDCl₃)δ8.5(m, 1H), 7.7(d, 1H, J=6 Hz), 7.5(m, 1H), 7.2(m, 1H), 7.15(m, 1H),7.05-6.95(m, 3H), 6.8(m, 1H), 6.75(br s, 1H), 4.07(s, 3H), 2.8(m, 2H),2.6(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃) 8 -75.96(s, 3F), -122.34(s, 1F).High resolution mass spec: calculated for C₂₁H₁₈N₃OF₄ (M+H)⁺: 404.1386,found 404.1385.

[0394] Step B: Preparation of compound VIII(R=(2-pyridyl)ethyl).

[0395] To a solution of VII (R=2-pyridylethyl)(15 mg, 0.037 mmol) inethanol (1 mL) was added a 48% aqueous solution of HBr (1 mL) and theresulting reaction mixture was allowed to stir at reflux for 5 hours.The reaction mixture is poured onto saturated NaHCO₃ and extracted withethyl acetate (3×25 mL). The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂,EtOAc eluant) provided 5 mg of the title compound (15 mg theoretical,36%). ¹H NMR (300 MHz, acetone-d₆) δ10.9(br s, 1H), 8.5(m, 1H), 8.3 (brs, 1H), 7.6(m, 1H), 7.4(m, 2H), 7.2-7.05(m, 3H), 7.0(d, 1H, J=7 Hz),6.4(d, 1H, J=7 Hz), 2.95(m, 2H), 2.6(m, 2H). ¹⁹F NMR (282 MHz,acetone-d₆) δ−76.49(s, 3F), -124.17 (s, 1F). High resolution mass spec:calculated for C₂₀H₁₆N₃OF₄ (M+H)⁺: 390.1221, found 390.1221.

Example 13 Compound VIIIa

[0396]

[0397] Step A: Preparation of compound VIIa.

[0398] To a solution of compound VII (R=n-propyl)(75 mg, 0.22 mmol) iniPrOH (2 mL) at room temperature was added NCS (30 mg, 0.22 mmol) andthe resulting reaction mixture was allowed to stir at reflux for 2hours. The reaction mixture was poured onto water and extracted withethyl acetate (2×50 mL). The combined ethyl acetate extracts were driedover anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂,10% EtOAc-hexanes eluant) provided 48 mg of compound VIla (82 mgtheoretical, 59%). ¹H NMR (300 MHz, CDCl₃) δ7.15(m, 1H), 7.0(m, 1H),6.95(m, 1H), 6.8(m, 1H), 6.6(br s, 1H), 2.3(m, 2H), 1.1(m, 2H), 0.95(m,3H). ¹⁹F NMR (282 MHz, CDCl₃) δ−76.05(s, 3F), −122.31 (s, 1F). Highresolution mass spec: calculated for C₁₇H₁₆ClN₃OF₄ (M+H)⁺: 375.0887,found 375.0883.

[0399] Step B: Preparation of compound of formula VIIa.

[0400] To a solution of VIIa (48 mg, 0.13 mmol) in ethanol (1 mL) wasadded a 48% aqueous solution of HBr (1 mL) and the resulting reactionmixture was allowed to stir at reflux for 1.5 hours. The reactionmixture is poured onto saturated NaHCO₃ and extracted with ethyl acetate(3×25 mL). The combined ethyl acetate extracts were dried over anhydrousMgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20%acetone-hexanes eluant) provided 14 mg of the title compound (47 mgtheoretical, 30%). ¹H NMR (300 MHz, acetone-d₆) δ8.4(br s, 1H), 7.4(m,1H), 7.3(m, 1H), 7.1(m, 1H), 6.6(m, 1H), 2.4(m, 2H), 1.1(m, 1H), 0.95(m,1H). ¹⁹F NMR (282 MHz, acetone-d₆) δ−76.58(s, 3F), −124.11(s, 1F). Anal.(C₁₆H₁₃N₂OClF₄) C, H, N.

Example 14 Compound VIII, wherein R=3-Propenyl

[0401]

[0402] Step A: Preparation of compound IX.

[0403] To a solution of compound VI (100 mg, 0.34 mmol) in ethanol (1mL) at room temperature was added a 48% aqueous solution of HBr (1 mL)and the resulting reaction mixture was allowed to stir at reflux for 1.5hours. The reaction mixture was diluted with water and filtered and thesolids were washed with water and dried in vacuo to give a yellow solid.Toluene was added to the solids and dried in vacuo to azeotrope tracesof water to provide 89 mg of compound IX (96 mg theoretical, 93%). ¹HNMR (300 MHz, DMSO-d₆) δ11.95(br s, 1H), 8.4(m, 1H), 7.95(m, 2H), 7.4(m,1H), 6.8(m, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−52.44(s, 3F), −105.16 (s,1F). High resolution mass spec: calculated for C₁₃H₇N₂OF₄ (M+H)⁺:283.0495, found 283.0492.

[0404] Step B: Preparation of compound of formula VIII (R=3-propenyl).

[0405] To a solution of IX (170 mg, 0.60 mmol) in THF (3 mL) at −78° C.was added a 1M solution of allyl magnesium bromide in ether (3.6 mL, 3.6mmol) and the resulting reaction mixture was allowed to stir at −78° C.for 15 minutes. The reaction mixture was quenched with saturated NH₄Cland poured onto water and extracted with ethyl acetate (2x50 mL). Thecombined ethyl acetate extracts were dried over anhydrous MgSO₄ andconcentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant)provided 37 mg of the title compound (195 mg theoretical, 19%). ¹H NMR(300 MHz, acetone-d₆) δ12.4(br s, 1H), 7.6(br s, 1H), 7.1(m, 1H),7.0-6.8(m, 3H), 6.4(d, 1H, J=7 Hz), 5.4(m, 1H), 5.0(m, 2H), 3.1(m, 2H).¹⁹F NMR (282 MHz, acetone-d₆) δ−75.83(s, 3F), −121.86(s, 1F). Anal.(C₁₆H₁₂N₂OF₄) C, H, N.

Example 15 Compound VIII, wherein R=2-Cyclopropyl-1-Ethyl

[0406]

[0407] Step B: Preparation of compound of formulaVIII(R=2-cyclopropyl-1-ethyl).

[0408] To a solution of 2-cyclopropylethyliodide (614 mg, 3.15 mmol) inhexanes (8 mL) at −78° C. was added a 1.7M solution of t-BuLi in THF(3.7 mL, 6.3 mmol) and the resulting reaction mixture was allowed tostir at −78° C. for 10 minutes. Ether (8 mL) was added and the reactionmixture was allowed to stir at room temperature for an hour. Thereaction mixture was cooled back down to −78° C. and THF (8 mL) wasadded followed by compound IX (178 mg, 0.63 mmol) and the resultingreaction mixture was allowed to stir at −78° C. for 30 minutes. Thereaction mixture was poured onto saturated NH₄Cl and thereafterpartitioned between ethyl acetate and water. The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 45 mg of thetitle compound (222 g theoretical, 20%). ¹H NMR (300 MHz, CDCl₃) δ12.55(br s, 1H), 7.6(br s, 1H), 7.2(m, 1H), 7.1-6.9(m, 3H), 6.45(d, 1H, J=7Hz), 2.5(m, 2H), l.l(m, 2H), 0.7(m, 1H), 0.5(m, 2H), 0.05(m, 2H). ¹⁹FNMR (282 MHz, CDCl₃) δ−75.80(s, 3F), −122.05(s, 1F). Anal. (C₁₈H₁₆N₂OF₄)C, H, N.

Example 16 Compound VIII, wherein R=Ethynyl

[0409]

[0410] Step B: Preparation of compound of formula VIII (R=ethynyl).

[0411] To a solution of trimethylsilylacetylene (432 μl, 3.06 mmol) inTHF (5 mL) at 0° C. was added a 1.6M solution of n-BuLi in THF (1.7 mL,2.72 mmol) and the resulting reaction mixture was allowed to stir at 0°C. for 30 minutes. Thereafter, compound IX (192 mg, 0.68 mmol) was addedas a suspension in THF (2 mL) and the resulting reaction mixture wasallowed to stir with warming to room temperature overnight. The reactionmixture was poured onto saturated NH₄Cl and thereafter partitionedbetween ethyl acetate and water. The combined ethyl acetate extractswere dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, EtOAc eluant) provided 74 mg of the trimethylsilylprotected compound (258 mg theoretical, 29%). ¹H NMR (300 MHz,acetone-d₆) δ11.2(br s, 1H), 8.8(br s, 1H), 7.45(m, 1H), 7.4(m, 1H),7.1(m, 1H), 7.05(m, 1H), 6.55(m, 1H), 0.05(s, 9H). ¹⁹F NMR (282 MHz,acetone-d₆) δ−77.59(s, 3F), −123.84(s, 1F). High resolution mass spec:calculated for C₁₈H₁₇N₂OSiF₄ (M+H)⁺: 381.1046, found 381.1055.

[0412] To a solution of the trimethylsilyl protected compound (74 mg,0.19 mmol) in methanol (1 mL) was added potassium carbonate (131 mg,0.95 mmol) and the resulting reaction mixture was allowed to stir atroom temperature overnight. The reaction mixture was poured onto waterand extracted with ethyl acetate (2×25 mL). The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, 50% EtOAc-hexanes eluant) provided 9 mg of thetitle compound (58 mg theoretical, 16%). ¹H NMR (300 MHz, acetone-d₆)δ11.0(br s, 1H), 8.6(br s, 1H), 7.5(m, 1H), 7.2(m, 1H), 7.1(d, 1H, J=7Hz), 6.6(d, 1H, J=7 Hz), 3.6(s, 1H). ¹⁹F NMR (282 MHz, acetone-d₆)δ−77.98(s, 3F), −123.95 (s, 1F). High resolution mass spec: calculatedfor C₁₅H₉N₂OF₄ (M+H)⁺: 309.065101, found 309.063882.

[0413] Example 17

Compound XIV, wherein R=2-Chloroethyl

[0414]

[0415] Step A: Preparation of compound X.

[0416] To a solution of acetonitrile (71 μl, 1.36 mmol) in THF (2 mL) at−78° C. was added a 2M solution of LDA in THF (0.76 mL, 1.52 mmol) andthe resulting reaction mixture was allowed to stir at −78° C. for 20minutes. Thereafter, compound VI (100 mg, 0.34 mmol) was added and theresulting reaction mixture was allowed to stir at −78° C. for 30minutes. The reaction mixture was poured onto saturated NH₄Cl andthereafter partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 100mg of compound X (115 mg theoretical, 87%). ¹H NMR (300 MHz, CDCl₃)δ7.8(d, 1H, J=7 Hz), 7.1(m, 2H), 6.9(m, 2H), 4.06(s, 3H), 3.5(m, 2H).¹⁹F NMR (282 MHz, CDCl₃) δ−76.48(s, 3F), −121.2(s, 1F). Anal.(C₁₆H₁₁N₃OF₄) C, H, N.

[0417] Step B: Preparation of compound XI.

[0418] To a solution of compound X (100 mg, 0.3 mmol) in dichloromethane(1.5 mL) at −78° C. was added a 1M solution of DIBAL in dichloromethane(0.45 mL, 0.45 mmol) and the resulting reaction mixture was allowed tostir at −78° C. for 2 hours. The reaction mixture was poured onto 20%KHSO₄ and thereafter partitioned between ethyl acetate and water. Thecombined ethyl acetate extracts were dried over anhydrous MgSO₄ andconcentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant)provided 43 mg of compound XI (102 mg theoretical, 42%). ¹H NMR (300MHz, CDCl₃) δ9.5(s, 1H), 7.7(d, 1H, J=7 Hz), 7.1(m, 2H), 6.85(m, 2H),4.07(s, 3H), 3,5(s, 2H). ¹⁹F NMR (282 MHz, CDCl₃) δ−76.66(s, 3F),−121.57(s, 1F). High resolution mass spec: calculated for C₁₆H₁₃N₂O₂F₄(M+H)⁺: 341.0913, found 341.0888.

[0419] Step C: Preparation of compound XII.

[0420] To a solution of compound XI (300 mg, 0.88 mmol) in ethanol (5mL) at room temperature was added sodium borohydride (100 mg, 2.64 mmol)and the resulting reaction mixture was allowed to stir at roomtemperature for 15 minutes. The reaction mixture was partitioned betweenethyl acetate and water. The combined ethyl acetate extracts were driedover anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂,20% EtOAc-hexanes eluant) provided 257 mg of compound XII (301 mgtheoretical, 85%). ¹H NMR (300 MHz, CDCl₃) δ7.7(d, 1H, J=7 Hz), 7.25(m,1H), 7.0(m, 2H), 6.8(m, 1H), 6.7(br s, 1H), 4.06(s, 3H), 3.5(m, 2H),2.7(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃) δ−76.51(s, 3F), −122.31(s, 1F).High resolution mass spec: calculated for C₁₆H₁₅N₂O₂F₄ (M+H)⁺: 343.1070,found 343.1072.

[0421] Step D: Preparation of compound XIII.

[0422] To a solution of compound XII (250 mg, 0.73 mmol) in acetonitrile(3 mL) at room temperature was added triphenyphosphine (289 mg, 1.10mmol) followed by carbon tetrachloride (4 mL) and the resulting reactionmixture was allowed to stir at room temperature overnight. The reactionmixture was partitioned between ethyl acetate and water. The combinedethyl acetate extracts were dried over anhydrous MgSO₄ and concentratedin vacuo to provide 210 mg of compound XIII (263 mg theoretical, 80%).¹H NMR (300 MHz, CDCl₃) δ7.75(d, 1H, J=7 Hz), 7.2(m, 1H), 7.1(m, 1H),6.95(m, 1H), 6.8(m, 1H), 6.75(br s, 1H), 4.06(s, 3H), 3.25(m, 2H),2.9(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃) δ−76.45(s, 3F), −121.76(s, 1F).High resolution mass spec: calculated for C₁₆H₁₄N₂OF₄Cl (M+H)⁺:361.0731, found 361.0748.

[0423] Step E: Preparation of compound XIV.

[0424] To a solution of compound XIII (52 mg, 0.144 mmol) in ethanol (1mL) at room temperature was added a 48% aqueous solution of HBr (1 mL)and the resulting reaction mixture was allowed to stir at reflux for 1.5hours. The reaction mixture is poured onto saturated NaHCO₃ andextracted with ethyl acetate (3×25 mL). The combined ethyl acetateextracts were dried over anhydrous MgSO₄ and concentrated in vacuo.Chromatography (SiO₂, 50% acetone-hexanes eluant) provided 45 mg ofcompound XIV (50 mg theoretical, 90%). ¹H NMR (300 MHz, CDCl₃) δ11.1(brs, 1H), 8.6(br s, 1H), 7.5-7.3(m, 2H), 7.1-7.0(m, 2H), 6.45(m, 1H),3.4(m, 2H(, 2.95(m, 2H). ¹⁹F NMR (282 MHz, CDCl₃) δ−76.75(s, 3F),−123.74(s, 1F).

[0425] Examples 18-26 can be made according to the following procedures.

Example 18

[0426]

[0427] Step A:

[0428] To a −78° C. solution of diisopropylamine (3.3 mL, 23.6 mmol) inTHF (100 mL) was added a solution of 1.6 M BuLi (16.1 mL, 23.6 mmol) inhexane. After the reaction was stirred for 0.5 h, a solution of3-chloro-2-methoxypyridine (3.4 g, 23.6 mmol) in THF (2 mL) was added.After stirring for 20 min., ketone (xv) was added. The reaction wasallowed to warm to −50° C., quenched with saturated NH₄Cl, diluted withEtOAc, and washed with 0.5 N HCl (3×), saturated NaHCO₃, and saturatedNaCl. The organic phase was dried over Na₂SO₄ and concentrated to anorange oil (17.5 g). The oil was triturated with CH₂Cl₂ (30 mL) to givea pale yellow solid (12.7 g, 97% yield) that was treated with TFA togive a detritylated product XVI (5.9 g, 77% yield).

[0429] Step B:

[0430] To a 120° C. suspension of Cs₂CO₃ (15 g) in DMSO (50 mL) wasadded a solution of XVI (5 g, 14.6 mmol) in DMSO (100 mL) dropwise over1.5 h, then heated at that temperature for 4 h. The reaction was cooledto room temperature and EtOAc (300 mL), water (150 mL) and 1 N HCl (200mL) were added. A yellow solid precipitated out and was filtered off andwashed with water and then EtOAc. The compound was dried at 100° C.under high vacuum overnight to give XVII (2.83 g, 75% yield).

[0431] Step C:

[0432] To a 0° C. suspension of XVII (2.83 g, 10.9 mmol) and SEM-Cl (6mL, 33.9 mmol) in DMF (100 mL) was added 60% NaH (1.33 g, 33.2 mmol) andthe reaction was stirred for 4 days. The reaction was diluted withEtOAc, washed with water (3×) and brine, and evaporated to give anorange oil (6.85 g). Chromatography and crystallization gave XVIII asyellow crystals (3.72 g, 87% yield).

[0433] Step D:

[0434] To a 0° C. solution of XVIII (700 mg, 1.79 mmol) and CF₃TMS (0.35mL, 2.37 mmol) in THF (7 mL) was added a solution of 1M TBAF in THF (0.2mL, 0.2 mmol). After 10 min., additional TBAF (0.3 mL, 0.3 mmol) wasadded to desilylate the silyl ether. After aqueous work-up, the crudeoil was triturated with hexanes to give XIX as an off-white solid (518mg, 63% yield).

[0435] Step E:

[0436] A solution of XIX (420 mg) in TFA was stirred for 1.5 h andconcentrated to give an oil. The oil was partitioned between EtOAc and 1N NaOH and washed with water and brine, and evaporated to give XX as ayellow solid (264 mg, 93% yield).

[0437] Alternative Method

[0438] Step A-2:

[0439] To a 0° C. solution of XVI (12 g, 32.7 mmol) and MeI (3.3 mL,53.5 mmol) in DMF (120 mL) was added 60% NaH (1.44 g, 36 mmol) andstirred overnight. After aqueous work-up, chromatography and triturationgave XXI (6.22 g, 50% yield).

[0440] Step B-2:

[0441] A solution of XXI (6.4 g, 16.8 mmol) in EtOH (20 mL) and asolution of 48% HBr (20 mL) was refluxed for 1.5 h. The reaction wasdiluted with EtOAc and neutralized, washed with brine, dried over Na₂SO₄and concentrated to an orange thick oil (8 g). Trituration with etherand CH₂Cl₂ gave XXII as a white solid (5.86 g, 95% yield).

[0442] Step C-2:

[0443] A suspension of XXII (4.7 g) in DMF (95 mL) was refluxed for 1.5h. EtOAc and water were added and the reaction was filtered and washedwith water (2×) and EtOAc (2×). The wet product was dried at 80° C.under high vacuum overnight to give XXIII as a yellow solid (2.85 g, 76%yield).

[0444] Step D-2:

[0445] A mixture of XX (1.5 g) in 48% HBr (10 mL) and EtOH (10 mL) wasrefluxed for 2 h. The reaction was diluted with water and neutralizedwith NaOH. The resulting solid was filtered off and washed withsaturated NaHCO₃ and water (2×), and dried at 100° C. under high vacuumovernight to give XXIII as a yellow solid (1.33 g, 93% yield).

[0446] Step F:

[0447] To a −78° C. solution of diisoproplylamine (1.08 mL, 7.68 mmol)in THF (10 mL) was added a solution of 1.6 M BuLi (4.921 mL, 7.78 mmol)in hexane. After the reaction was stirred for 15 min., 2-picoline (7.59mL, 7.68 mmol) was added. After stirring for 20 min., XX (600 mg, 1.92mmol) was added. The reaction was quenched with saturated NH₄Cl, thendiluted with EtOAc, washed with 0.1 N HCl (4×), water and saturatedNaCl. The organic phase was dried over Na₂SO₄ and concentrated to a darkorange glass (670 mg). Flash chromatography (50% EtOAc/hexanes) gaveXXIV (R=2-picolyl (2-pyridylmethyl)) (R =2-picolyl (2-pyridylmethyl) asa thick pink oil (R=2-picolyl, 600 mg, 70% yield).

[0448] Step G:

[0449] A solution of XXIV (R=2-picolyl (2-pyridylmethyl)) 1.53 g) in 48%HBr (7 mL) and EtOH (7 mL) was refluxed for 1.5 h. The reaction wasdiluted with EtOAc and THF and neutralized with 1 N NaOH, and washedwith brine. The organic phase was dried over Na₂SO₄ and evaporated togive a gray solid (1.32 g). The solid was triturated with boilingdichloroethane (10 mL) to give XXV (1.25 g).

Example 21

[0450] A solution of XXIV ((R=cyclopropyl acetylene, 56 mg), DIEA (15uL) and a solution of 1 M TMS-I in methylene chloride (1 mL) inmethylene chloride (5 mL) was stirred overnight. The reaction wasdiluted with EtOAc and washed with 1 N NaOH and brine. The organic phasewas dried over Na₂SO₄ and evaporated to give an orange glass (64 mg).The glass was triturated with ether (2 mL) to give XXV (R=cyclopropylacetylene) as off-white solid (7.5 mg).

Example 24 (XXV, Single Active Enantiomer)

[0451] To a 0° C. solution of XXV (R=2-picolyl (2-pyridylmethyl), 100mg, 0.26 mmol) in DMF (2 mL) was added 60% NaH (11.2 mg, 0.28 mL). Afterstirred for 20 min., MeI (25 uL, 0.4 mmol) was added. After stirring for10 min., the reaction was diluted with EtOAc and washed with water (2×)and brine. The organic phase was dried over Na₂SO₄ and evaporated togive a brown solid (127 mg). The solid was triturated with ether (2 mL)to give XXVI as a pale orange solid (81 mg, 84% yield).

Example 20

[0452] To a −78° C. solution of 85% cyclopropylethyl iodide (9.66 g,41.5 mmol) in hexanes (75 mL) was added a solution of 1.7 M t-BuLi inpentane (49.3 mL, 83.8 mmol). After 5 min., ether (75 mL) was added andthe reaction was warmed to room temperature for 1 h to destroy anyexcess of t-BuLi. The reaction was cooled back to −78° C. and THF (20mL) was added. This −78° C. reaction mixture was added to a −78° C.suspension of XXIII (2.5 g, 8.38 mmol) in THF (100 mL) and TMEDA (10mL). The reaction was quenched with saturated NH₄Cl, then diluted withEtOAc, washed with 1 N HCl, water and saturated NaCl. The organic phasewas dried over Na₂SO₄ and concentrated to an orange oil. Flashchromatography (25-50% EtOAc/hexanes) and trituration (dichloroethaneand hexanes) gave XXV as a brown solid (R=cyclopropylethyl, 1.76 g, 58%yield).

Example 22

[0453]

[0454] The compound XXVIII (R=cyclopropylaminomethyl) was made by themethod described in Example 30, below.

Example 28

[0455]

[0456] Step A:

[0457] A suspension of XXIII (17.5 g) and NaCN (5.86 g) in DMF (450 mL)was stirred for 3 days. The reaction was diluted with EtOAc and washedwith saturated NaHCO₃, water and brine. The organic phase was dried overNa₂SO₄ and concentrated to a gray solid which triturated with methylenechloride (20 mL) to give a yellow solid XXXV (14.2 g, 72% yield). Thecompound XXXV was treated with DIBAL in methylene chloride at −78° C. togive a brown solid (14.2 g) after 3 N HCl/EtOAc workup. The crude solidwas triturated with methylene chloride (20 mL) to give a yellow solidXXXIV (9.7 g, 69% yield).

[0458] Step B:

[0459] A suspension of XXXIV (5 g) and TsOH (4.6 g, 2 eq) in i-PrOH (100mL) and (i-PrO)₃CH (40 mL) was stirred for 45 min. The reaction wasdiluted with EtOAc and washed with 1 N NaOH, water and brine. Theorganic phase was dried over Na₂SO₄ and concentrated. Flashchromatography (75% EtOAc/hexanes) and trituration (ether and hexanes)gave a pale yellow solid XXXVII (3.7 g, 70% yield).

[0460] Step C:

[0461] A solution of XXXVII (3.5 g) in Et₃SiH (70 mL), CH₂C₁₂ (35 mL)and TFA (70 mL) was stirred overnight and solvents were evaporated. Thereaction was diluted with EtOAc and washed with 1 N NaOH, water andbrine. The organic phase was dried over Na₂SO₄ and concentrated. Flashchromatography (75% EtOAc/hexanes) and trituration (ether and hexanes)gave a pale yellow solid XXXVIII (1.9 g, 60% yield).

Example 30

[0462]

[0463] A suspension of XXXVI (2.89 g), isopropylamine (4.5 mL) andacetic acid (9 mL) in toluene (440 mL) was stirred for 4 days. ThenNaCNBH₃ (0.6 g) and MeOH (44 mL) were added to the reaction. Afterstirring for 2.5 h, The reaction was diluted with EtOAc and washed withsaturated NaHCO₃, water and brine. The organic phase was dried overNa₂SO₄ and concentrated to a yellow solid XXXIX (2.3 g, 68% yield).

Example 37

[0464]

[0465] The compound of Example 18 (2.13 grams) was dissolved in 150 mlof N,N-dimethylacetamide. 1,1′-bis(diphenylphosphino)ferrocene (1.33 g,0.4 equivalents), zinc cyanide (1.40 g, 2.0 equivalents) and zinc powder(0.47 g 1.2 equivalents) were added. The mixture was degassed under highvacuum, and then 1.09 g (0.2 equivalents) oftris(dibenzylideneacetone)dipalladium(0) was added. The mixture wasdegassed once again, and heated to reflux for 18 hours. The blackmixture was cooled and partitioned between ethyl acetate and 2N ammoniumhydroxide. Both phases were filtered through Celite and separated. Theorganic phase was washed twice with water and dried over magnesiumsulfate. Flash chromatography (silica gel, 50% EtOAc/hexane) yielded1.44 g (69% yield) of compound XL as a brown solid M.S. 346.2 (M-H)⁻.

Example 38

[0466]

[0467] Pyridone XXXVIII (2.92 grams) was dissolved in 75 ml ofN-methylpyrrolidinone. 1.92 g (2.0 equivalents) of zinc cyanide and 1.18g (2.2 equivalents) of zinc powder were added. The mixture was degassedunder high vacuum, and then 7.34 g (1.1 equivalents) ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct was added. The mixture was degassed once again,and heated to 170° C. 18 hours. The mixture was cooled and partitionedbetween ethyl acetate and 2N ammonium hydroxide. Both phases werefiltered through Celite and separated. The organic phase was washedtwice with water and dried over magnesium sulfate. Flash chromatography(silica gel, 50% EtOAc/hexane) yielded 1.76 g (59% yield) of compoundXLI as a brown solid, M.S. 362.2 (M-H)⁻.

[0468] The 4-alkylthiomethyl derivatives were synthesized using thesynthetic Scheme shown below. Sulfoxide XLII was deprotonated with astrong base, such as lithium, sodium or potassium diisopropylamide or asimilar amine anion in an inert solvent such as THF to give thecorresponding deprotonated species. This was added to the pyridone coreXXIII, to form a mixture of diastereomers XLIII at temperature rangesfrom −78 to 25° C. The diastereomeric mixture or each individualdiastereomer was deoxygenated by an appropriate reagent such as TiI₄ inan inert solvent such as acetonitrile by the process described byShimizu et al. Synlett. 2000, 1437, to give the corresponding sulfide.

Example 39 (Compound XLIV wherein R³a is Cl, R is Cyclopropyl)

[0469] Step A:

[0470] Cyclopropylmethyl sulfoxide: Cyclopropylbromide (8 mL, 0.1 mol)in ether (10 mL) was added dropwise into a suspension of Mg turnings(2.43 g, 0.1 mol) in ether (90 mL). After the addition was over thereaction was stirred at 25° C. for 3 hours and heated at reflux for 3hours. Then it was cooled to 0° C. and (CH₃S)₂ (9 mL, 0.1 mol) was addeddropwise and the mixture was stirred at 0° C. for 1 hour, at 25° C. for20 hours and at reflux for 3 hours. After cooling it was quenched withwater (5 mL) and 5% HCl (3 mL). The precipitated solids were filteredoff and the filtrate was washed with water, brine, dried (MgSO₄), anddistilled at atmospheric pressure. The fraction distilled at 100-110° C.consisted of a 1:1 mixture of cyclopropylmethylsulfide and methyldisulfide (4.4 g).

[0471] Step B:

[0472] Two grams of the above mixture (˜22.2 mmol) in CH₂Cl₂ (50 mL) wascooled to −5° C. in a salt/ice bath and 4 g m-chloroperbenzoic, 70-75%acid was added in potions. The reaction was stirred at −5° C. for 2hours and at 25° C. for 20 hours. Then it was quenched with satNaHCO₃,satNa₂S₂O₅, diluted with CH₂Cl₂ (50 mL) and washed with satNaHCO₃ (2×30mL), brine, dried and stripped in vacuo. NMR analysis of the cruderesidue indicated that it consisted of the product, cyclopropyl methylsulfoxide and ˜10% of the corresponding sulfone. ¹H NMR(CDCl₃) 2.66 (s,3H), 2.14-2.19 (m, 1H), 0.8-1.22 (m, 4H).

[0473] Step C:

[0474] To a solution of diisopropylamine (0.22 mL, 1.64 mmol in THF (3mL) at −78° C. (dry ice/acetone bath) a 1.6 solution of nBuLi in hexanes(0.84 mL, 1.36 mmol) was added and the mixture was warmed to 0° C.,stirred for 10 min and cooled back to −78° C. To the solution of LDAformed, cyclopropyl methyl sulfoxide (1.42 mg, 1.36 mmol) in THF (3 mL)was added and the reaction mixture was stirred at −78° C. for 30 min.Then the temperature was adjusted at −40° C. (acetonitrile/dry ice bath)and pyridone XXIII (100 mg, 0.34 mmol) was added as a solid. Thereaction was stirred at −40° C. for 3 hours, quenched with 10% NH₄Cl andpartitioned between EtOAc (100 mL) and brine (20 mL). The EtOAc extractwas dried and stripped in vacuo. The residue was chromatographed onsilica gel using EtOAc 1% methanol/EtOAc and 5% methanol/EtOAc to givethe product. This was washed with ether to give the sulfoxide adductXLIII as a mixture of diastereomers (47 mg).

Example 39a

[0475] Step D:

[0476] The diastereomeric mixture of the sulfoxides from the previousreaction (43 mg, 0.11 mmol) was added into a mixture of TiI₄ (93 mg,0.17 mmol) in acetonitrile (2 mL) at 0° C. The reaction was stirred at0° C. for 45 min and quenched with satNaHCO₃ (10 mL) and satNa₂S₂O₅ (5mL). Then it was partitioned between EtOAc (100 mL) and water (20 mL),The EtOAc was washed with brine, dried (MgSO4), and stripped in vacuo.The crude product was purified by column chromatography using EtOAc and2% methanol/EtOAc to give XLIV (26 mg). ¹H NMR(CDCl₃): 10.7-10.8 (br s,1H), 7.40 (br s, 1H), 7.25 (dd, 1 H, J=2.2, 8.8 Hz), 6.89 (d, 1H, J=7.3Hz), 6.83 (d, 1H, J=8.8 Hz), 6.32 (d, 1H, J=7.3 Hz), 3.64 (d, 1H, J=13.9Hz), 3.55 (d, 1H, J=13.9 Hz), 1.48-1-58 (m, 1H), 0.76-0.80 (m, 2H),0.42-0.47 (m, 2H).

[0477] Examples 40-46 were prepared using the procedure described inExample 39.

Example 40 Compound XLIII (R^(3a) is Chloro and R is I-propyl)

[0478] The compound was prepared as described above. The compound waschromatographed on silica gel. The eluent used was a gradient of 90 %ethyl acetate/hexane to ethyl acetate to afford one diastereomer, brownsolid, 59 mg, mp 238° C. (decomp). Yield 27%. APCI-MS calcd. forC₁₇H₁₆ClF₃N₂O₂S (404.057): (M+H+CH₃CN)⁺=446.0, 100%. ¹H NMR (DMSO):11.8-11.9 (d, 1H); 9.3 (s, 1H); 7.5 (s, 1H); 7.33 (d, 1H, J=8.8 Hz);7.25 (d, 1H J=7.0 Hz,); 6.92 (t, 1H); 6.33 (d, 1H, J=7.0 Hz); 3.84 (d,2H, J=4.1 Hz); 2.95 (m, 1H); 1.20 (d, 3H, J=7.0 Hz); 1.13 (d, 3H J=6.9Hz).

[0479] Chromatographed using the same conditions as in to afford theother diastereomer, yellow solid, 63 mg, 223° C. (decomp). Yield 28 %.APCI-MS calcd. For C₁₇H₁₆ClF₃N₂O₂S (404.057): (M+H+CH₃CN)⁺=446.0, 100%.¹H NMR (DMSO): 11.7 (d, 1H); 9.29 (s, 1H); 7.55 (s, 1H); 7.38 d, 1H,J=8.8 Hz); 7.31 (d, 1H, J=1.9 Hz); 6.8 (t, 1H); 6.3-6.4 (d, 1H); 3.6-4.0(doublet of doublets, 2H); 2.9 (m, 1H); 1.18 (d, 3H, J=6.6 Hz); 1.13 (d,3H, J=7 Hz).

Example 41 (Compound XLIII wherein R³a is Chloro and R is T-butyl)

[0480] The compound was chromatographed on silica gel. The eluent usedwas a gradient of 90% ethyl acetate-hexane to 5% methanol/ethyl acetateto afford the diastereomer, which was washed with ether/hexanes to givea light yellow solid, 15 mg, 193° C. (decomp). Yield 13%.

[0481] APCI-MS calcd. for C₁₈H₁₈ClF₃N₂O₂S (418.073): (M+H+CH₃CN)⁺=460.1,100%.

[0482] The compound was chromatographed on silica gel. The eluent usedwas a gradient of 90% ethyl acetate-hexane to 5% methanol/ethyl acetateto afford the other diastereomer, which was recrystallized from ethylacetate/methanol/hexanes to give a light brown solid, 9 mg. Yield 8%.

[0483] APCI-MS calcd. for C₁₈H₁₈ClF₃N₂O₂S (418.073): (M+H+CH₃CN)⁺=460.1,100%.

Example 42 (Compound XLIV wherein R³a is Chloro and R is Methyl)

[0484] Synthesized in a similar manner as described earlier. The crudereaction product was washed with ether and had a purity of 95% by HPLCanalysis (82% yield). ¹H NMR(dmso) 11.82 (brs, 1H), 9.25 (brs, 1H), 7.55(brs, 1H), 7.34 (d, 1H, J=8.7 Hz), 7.27 (dd, 1H, J=2.2, 8.7 Hz), 6.91(d, 1H, J=6.9 Hz), 6.4 (d, 1H, J=6.9 Hz), 3.82 (d, 1H, J=13.5 Hz), 3.59(d, 1H, J=13.5 Hz), 2.00 (s, 3H)

Example 43 (Compound XLIV wherein R³a is Chloro and R is Ethyl)

[0485] Purified by silica gel chromatography (EtOAc eluent, 75% yield).¹H NMR(CDCl₃): 7.4 (brs, 1H), 7.35 (brs, 1H), 7.24 (dd, 1H, J=2.2, 8.2Hz), 6.92 (d, 1H), 6.83 (d, 1H, J =8.2 Hz), 6.35 (d, 1H), 3.4-3.6 (d,d2H), 2.48 (q, 2H), 1.20 (t, 3H).

Example 44 (Compound_XLIV wherein R³a is Chloro and R is I-propyl)

[0486] Pale yellow solid, 30 mg. mp =220-221° C. Yield 76 %. APCI-MScalcd. for C₁₇H₁₆ClF₃N₂OS (388.062): (M+H+CH₃CN)⁺=430.1, 88%.

Example 45 (Compound XLIV wherein R³a is Fluoro and R is I-propyl)

[0487] Orange solid, 14 mg. mp=215-216° C. Yield 40%. APCI-MS calcd. forC₁₇Hl₆F₄N₂OS (372.092): (M+H+CH₃CN)+=414.1, 100%.

Example 46 (Compound XLIV wherein R³a is Chloro and R is T-butyl)

[0488] White solid, 9 mg. mp=247-249° C. Yield 36%. APCI-MS calcd. forC₁₈H₁₈ClF₃OS (402.078): (M+H+CH₃CN)⁺=444.1, 100%.

Example 47 (Compound CVI)

[0489]

[0490] Step A: Preparation of compound CII.

[0491] To a 50° C. solution of 20.8 g of phosphorous pentachloride in150 mL of chloroform was added 2.97 g of 2-piperidone (CI) dropwise over15 min. The reaction mixture was warmed to 75° C. and stirred at thattemperature for 4.5 h. The cooled reaction mixture was slowly pouredonto 150 mL of ice water with vigorous stirring keeping the temperaturefrom 25-30° C. After stirring an additional 15 min, the mixture wasextracted with methylene chloride and the extracts were washed firstwith aqueous sodium bicarbonate then brine, dried over sodium sulfate,and evaporated to afford 4.5 g of CII as a pure solid.

[0492] Step B: Preparation of compound CV.

[0493] A mixture of 4.39 g of 3,3-dichloropiperidone (CII) and 13 ml ofmorpholine was heated at 128° C. for 2 h and then evaporated to dryness.The crude morpholine enamine (CIII) thus obtained was combined with 6.43g of CIV and 60 ml of acetic acid and was stirred for 6 h at reflux andovernight at room temperature. Evaporation of the solvent followed bytrituration with water afforded a solid product which afterrecrystallization from ethyl acetate/hexane afforded 6.27 g of CV.

[0494] Step C: Preparation of compound XXIII.

[0495] A mixture of 500 mg of CV, 700 mg of 3-iodylbenzoic acid(prepared as described by Barton, 1982, J. Chem. Soc. Perkin Trans. I,1947-1952), 30 mg of benzeneseleninic acid (70%, from Aldrich ChemicalCo.) and 35 mL of dry toluene was refluxed for 19 h. The mixture wasevaporated to dryness, 80 mL of aqueous sodium bicarbonate was added,and the mixture was stirred vigorously for 30 min. The yellow solid wascollected, washed with water and methanol to afford 390 mg of XXIII asbright yellow crystals.

[0496] Step D: Preparation of tributyl (cyclopropylmethoxymethyl)tin.

[0497] To a solution of 1.15 g of cyclopropyl carbinol in 30 mL of dryTHF was added 312 mg of 98% sodium hydride. After stirring 1 h, 2.8 g ofiodomethyl tributyltin (prepared as described by Seitz et al, 1983Synthetic Commun. 13, 129) was added and the reaction mixture wasstirred at room temperature for 24 h, and then poured onto water andextracted with hexanes. The extracts were washed with brine, dried andevaporated to a crude product that was purified by flash chromatography(hexanes then 30% ethyl acetate/hexanes eluents) to afford 1.03 g oftributyl (cyclopropylmethoxymethyl)tin as a colorless oil.

[0498] Step E: Preparation of compound CVI.

[0499] To a −78° C. solution of 565 mg of tributyl(cyclopropylmethoxymethyl)tin and 0.5 ml of TMEDA in 5 mL of anhydrousTHF was added 0.53 ml of 2.5M butyllithium in hexane. After 5 min, 100mg of XXIII was added in a single portion, and the stirred suspensionwas stirred at −50° C. for 45 min. The cold reaction mixture wasquenched by the addition of aqueous ammonium chloride, and thenextracted with ethyl acetate. The extracts were washed with brine, driedover sodium sulfate, and evaporated to an oily solid which wastriturated with hexane to remove the tetraalkyltin byproduct. The crudesolid was purified by preparative tlc (75% EtOAc/hexanes eluent) to giveafter crystallization (CH₂Cl₂/EtOAc/hexanes) 23 mg of CVI (mp 250° C.).

Example 48 (Compound CVII)

[0500]

[0501] Step A: Preparation of tributyl (cyclobutyloxymethyl)tin.

[0502] To a solution of 2.3 g of cyclobutanol in 60 mL of dry THF wasadded 624 mg of 98% sodium hydride. After stirring 2 h, 5.6 g ofiodomethyl tributyltin (prepared as described by Seitz et al 1983Synthetic Comm. 13 129) was added and the reaction mixture was stirredat room temperature for 48 h, and then poured onto water and extractedwith hexanes. The extracts were washed with brine, dried and evaporatedto a crude product that was purified by flash chromatography (hexanesthen 67% ethyl acetate/hexanes eluents) to afford 1.64 g of tributyl(cyclobutyloxymethyl)tin as a colorless oil.

[0503] Step B: Preparation of compound CVII.

[0504] To a −78° C. solution of 565 mg of tributyl(cyclobutyloxymethyl)tin and 0.5 ml of TMEDA in 5 mL of anhydrous THFwas added 0.625 ml of 1.6 M butyllithium in hexane. After 5 min, 75 mgof XXIII was added in a single portion, and the stirred suspension wasstirred at −50° C. for 40 min. The cold reaction mixture was quenched bythe addition of aqueous ammonium chloride, and then extracted with ethylacetate. The extracts were washed with brine, dried over sodium sulfate,and evaporated to an oily solid which was triturated with hexane toremove the tetraalkyltin byproduct. The crude solid was purifiedpreparative tlc (75% EtOAc/hexanes eluent) to give 11.3 mg of CVII (mp245° C.).

Example 49 Compound CVIII

[0505]

[0506] To a −78° C. solution of 565 mg of tributylcyclobutyloxymethyltin and 0.5 ml of TMEDA in 5 mL of anhydrous THF wasadded 0.626 ml of 1.6 M butyllithium in hexane. After 5 min, 100 mg ofIX was added in a single portion, and the stirred suspension was stirredat −50° C. for 40 min. The cold reaction mixture was quenched by theaddition of aqueous ammonium chloride, and then extracted with ethylacetate. The extracts were washed with brine, dried over sodium sulfate,and evaporated to an oily solid which was triturated with hexane toremove the tetraalkyltin byproduct. The crude solid was purified bypreparative tlc (75% EtOAc/hexanes eluent) to give 12 mg of CVIII (mp224°C.)

Example 50 Compound CIX

[0507]

[0508] To a −78° C. solution of 800 mg of tributylcyclopropylmethoxymethyltin and 0.7 ml of TMEDA in 7 mL of anhydrous THFwas added 0.90 ml of 1.6 M butyllithium in hexane. After 5 min, 100 mgof IX was added in a single portion, and the stirred suspension wasstirred at −50° C. for 40 min. The cold reaction mixture was quenched bythe addition of aqueous ammonium chloride, and then extracted with ethylacetate. The extracts were washed with brine, dried over sodium sulfate,and evaporated to an oily solid which was triturated with hexane toremove the tetraalkyltin byproduct. The crude solid was purified bypreparative tic (75% EtOAc/hexanes eluent) to give 20 mg of CIX as acrystalline solid (mp 203-204° C.).

Example 51 Compound CXVIII

[0509]

[0510] Step A: Preparation of compound CXI.

[0511] To a 50° C. solution of 31.9 g of phosphorous pentachloride in225 mL of chloroform was added 5.2 g of 6-methyl-2-piperidone (CX)portionwise over 15 min. The reaction mixture was warmed to 75° C. andstirred at that temperature for 4.5 h. and then at room temperatureovernight. The cooled reaction mixture was slowly poured onto 225 mL ofice water with vigorous stirring keeping the temperature from 25-30° C.After stirring an additional 10 min, excess aqueous sodium bicarbonatewas added and after 10 min, the mixture was extracted with methylenechloride and the extracts were washed with brine, dried over sodiumsulfate, and evaporated to afford 6.7 g of CXI as a pure solid.

[0512] Step B: Preparation of compound CXIII.

[0513] A mixture of 1.56 g of 6-methyl-3,3-dichloropiperidone (CXI) and4.5 ml of morpholine was heated at 128° C. for 2 h and then evaporatedto dryness.

[0514] The crude morpholine enamine (CXII) thus obtained was combinedwith 2.14 g of CIV and 20 ml of acetic acid and was stirred for 3 h atreflux, and at room temperature overnight. Evaporation of the solventfollowed by trituration with water afforded a solid product which afterrecrystallization from ethyl acetate/hexane afforded 1.86 g of CXIII.

[0515] Step C: Preparation of compound CXIV.

[0516] A mixture of 1.5 g of CXIII, 850 mg of N-bromosuccinimide, and150 mg of Vazo52 in 250 ml of carbon tetrachloride was refluxed for 1 hand the solvent was removed on the rotary evaporator. Recrystallizationof the crude product afforded 680 mg of CXIV as yellow crystals.

[0517] Step D: Preparation of compound CXV.

[0518] A mixture of 1.28 g of CXIV, 250 mg of sodium cyanide, and 25 mLof DMF was stirred at room temperature for 22 h. The reaction mixturewas diluted with ethyl acetate, washed three times with water, driedover sodium sulfate and evaporated. Recrystallization from ether/hexaneafforded 1.07 g of CXV.

[0519] Step E: Preparation of compound CXVI.

[0520] To a suspension of 500 mg of CXV in 50 ml of anhydrous methylenechloride at −78° C. was added dropwise 6.6 mL of 1M diisobutylaluminumhydride in toluene. After 2 h at −78° C. the cold reaction mixture waspoured onto a mixture of 250 mL of 3N HCl and 250 ml of ethyl acetatewhich was stirred for 10 min. The organic layer was washed with aqueoussodium bicarbonate, dried over sodium sulfate, and evaporated to 508 mgof CXVI.

[0521] Step F: Preparation of compound CXVII.

[0522] A mixture of 900 mg of CXVI, 180 mg of p-toluenesulfonic acid, 10mL of triisopropyl orthoformate, and 10 mL of isopropanol. was stirredat room temperature for 1 h. The reaction mixture was diluted with ethylacetate, washed 3X with 0.1N NaOH, water, then brine, dried over sodiumsulfate and evaporated to a crude oil that was purified by flashchromatography (67% EtOAc/hexanes) to afford 600 mg of CXVII.

[0523] Step G: Preparation of compound CXVIII.

[0524] A mixture of 583 mg of CXVII, 6 mL of triethylsilane, 12 mL oftrifluoroacetic acid, and 12 ml of dry methylene chloride was stirredovernight at room temperature and then evaporated to dryness. The crudeproduct was dissolved in ethyl acetate, washed twice with aqueous sodiumbicarbonate then brine, dried over sodium sulfate and evaporated to 570mg of a solid. This was dissolved in a hot mixture of ethyl acetate andmethylene chloride and the cooled solution deposited 140 mg of acrystalline byproduct. The mother liquor was subjected to flashchromatography on silica gel (eluted with 33%, 50%, and 67%ethylacetate/hexane) to afford 235 mg of CXVIII as colorless crystals(mp 234-235° C.).

Example 52 Compound CXIX

[0525]

[0526] To a −78° C. mixture of 107 mg of CXIV in 10 mL of dry THF and 1mL of TMEDA was added dropwise 1.0 mL of 1.6 M butyllithium and themixture was stirred 30 min at −78° C. The cold reaction mixture wasquenched by the addition of aqueous citric acid, and then extracted withethyl acetate. The extracts were washed with brine, dried over sodiumsulfate, and evaporated to an oil that was purified by flashchromatography (33% EtOAc/hexanes eluent) to give afterrecrystallization from ether/hexanes 60 mg of CXIX as a crystallinesolid (mp 206-208° C).

Example 53 Compound CXX

[0527]

[0528] A degassed mixture of 41 mg of CXIX, 26 mg of zinc cyanide, 90 mgof Pd(dppf)Cl₂.CH₂Cl₂, 16 mg of zinc powder, and 1.5 mL ofN-methylpyrrolidone was stirred under nitrogen for 25 h at 150° C. Thecooled mixture was diluted with ethyl acetate and filtered through a padconsisting of layers of sand, silica gel, and celite. The filtrate waswashed with 2N NaOH and brine, dried over sodium sulfate and evaporated.Flash chromatography (50% EtOAc/hexanes eluent) gave afterrecrystallization from ethyl acetate/hexanes 16 mg of CXX as acrystalline solid (mp 254-255° C.).

Example 54 Compound CXXV

[0529]

[0530] Step A: Preparation of compound CXXII.

[0531] To a 50° C. solution of 20.8 g of phosphorous pentachloride in150 mL of chloroform was added 3.39 mL of 1-methyl-2-piperidone (CXXI)dropwise over 15 min. The reaction mixture was warmed to 75° C. andstirred at that temperature for 4.5 h. The cooled reaction mixture wasslowly poured onto 150 mL of ice water with vigorous stirring keepingthe temperature from 25-30° C. After stirring an additional 15 min, themixture was extracted with methylene chloride and the extracts werewashed first with aqueous sodium bicarbonate then brine, dried oversodium sulfate, and evaporated to afford 5.0 g of CXXII as a pure oil.

[0532] Step B: Preparation of compound CXXIV.

[0533] A mixture of 1.0 g of CXXII and 5 ml of morpholine was heated at128° C. for 1.25 h and then evaporated to dryness. The residue wasdissolved in methylene chloride, washed with water and aqueous citricacid, dried and evaporated to 0.5 g of CXXIII as an oil.

[0534] The crude morpholine enamine (CXXIII) thus obtained was combinedwith 500 mg of CIV and 9 ml of acetic acid and was stirred at reflux for4.5 h. After evaporation of the solvent, the crude product waspartitioned between methylene chloride and water and the organic layerwas washed with aqueous sodium bicarbonate, dried, evaporated andpurified by flash chromatography (10% MeOH/methylene chloride) to give453 mg of CXXIV as a solid product.

[0535] Step C: Preparation of tributyl (isopropoxymethyl)tin

[0536] To a solution of 4.6 mL diisopropylamine in 40 mL of dry THF at−20° C. was added dropwise first 12.0 ml of 2.5 M butyllithium and then8.1 ml of tributyltinhydride. After 10 min this solution was cooled to−78° C., and 3.25 g of chloromethyl isopropyl ether (Molina et al, 1982Synthesis, 944) was added dropwise. After 10 min the cooling bath wasremoved and the reaction mixture was stirred at ambient temperature for1.5 h. The mixture was poured onto water and extracted with hexanes andthe extracts were dried over sodium sulfate and evaporated. The crudeproduct was distilled (0.2 mm, 110-130° C.) to afford 7.8 g of tributyl(isopropoxymethyl)tin as a colorless liquid.

[0537] Step D: Preparation of compound CXXV.

[0538] To a −78° C. solution of 719 mg of tributyl (isopropoxymethyl)tinand 0.4 ml of TMEDA in 4 mL of anhydrous THF was added 0.53 ml of 2.5Mbutyllithium in hexane. After 5 min, 100 mg of XXIV was added in asingle portion, and the stirred suspension was allowed to stir at −78°for 45 min. The cold reaction mixture was quenched by the addition ofaqueous ammonium chloride, and then extracted with ethyl acetate. Theextracts were washed with brine, dried over sodium sulfate, andevaporated to an oily solid. The crude solid was purified by flashchromatography (50% EtOAc/hexanes eluent) and then preparative tic (50%EtOAc/hexanes eluent) to give 2 mg of CXXV [ms, (m+H)⁺=389.0]

Example 55 Compound CXXVI

[0539]

[0540] To a −78° C. mixture of 225 mg of CXXIV in 20 mL of dry THF and 2mL of TMEDA was added dropwise 1.22 mL of 2.5 M butyllithium and themixture was stirred 30 min at −78° C. The cold reaction mixture wasquenched by the addition of aqueous ammonium chloride, and thenextracted with ethyl acetate. The extracts were washed with 1N HCl,water, brine, dried over sodium sulfate, and evaporated to an oil thatwas purified by flash chromatography (10-20% EtOAc/hexanes eluent) andpreparative tic (50% EtOAc/hexanes eluent) to give 7 mg of CXVII as acrystalline solid (mp 221-223° C.).

Example 56 Compound CXXVII

[0541]

[0542] To a −78° C. solution of 1.07 mL of diisopropylamine in 10 mL ofdry THF was added dropwise 3.1 mL of 2.5 M butyllithium. After 15 min,0.755 mL of 2-methylpyridine was added, andthe mixture was stirred 20min at −78° C. 600 mg of CXXIV was added, and after 30 min, the coldreaction mixture was quenched by the addition of aqueous ammoniumchloride, and then extracted with ethyl acetate. The extracts werewashed with 0.lN HCl, water, brine, dried over sodium sulfate, andevaporated to an oil that was purified by flash chromatography (50%EtOAc/hexanes then 5% MeOH/CH₂Cl₂ eluent) and preparative tlc (5%MeOH/CH₂Cl₂ eluent)) to give after recrystallization from methylenechloride/hexanes 60 mg of CXXVII as a crystalline solid (mp 192-193°C.).

Example 57 Compound CXXX

[0543]

[0544] Step A: Preparation of compound CXXVIII.

[0545] To a −78° C. solution of 0.45 mL ofdiisopropylamine in 10 mL ofdry THF was added dropwise 0.90 mL of 1.6 M butyllithium. After 15 min,0.45 mL of tert-butylacetate was added dropwise, and the mixture wasstirred 30 min at −78° C. then allowed to warm to 0° C. The reactionmixture was again cooled to −78° C., 315 mg of CXXIV dissolved in 8 mLof THF was added dropwise, and it was stirred 30 min at −78° C. and 30min at 0° C. The cold reaction mixture was quenched by the addition ofaqueous ammonium chloride, and then extracted with ethyl acetate. Theextracts were washed with water and brine, dried over sodium sulfate,and evaporated to 400 mg of CXXVIII as a pure solid.

[0546] Step B: Preparation of CXXIX.

[0547] A mixture of 183 mg of CXXVIII, 12 ml of methylene chloride, and4.0 mL of trifluoroacetic acid was stirred for 1 h at 50° C. The cooledreaction mixture was poured onto water and extracted with methylenechloride. After drying over sodium sulfate, the extracts were evaporatedto give 183 mg of CXXIX as a pure solid.

[0548] Step C: Preparation of CXXX.

[0549] A solution of 30 mg of CXXIX, 0.100 mL of thionyl chloride, and2.0 mL of methanol was stirred overnight at room temperature. Thereaction mixture was diluted with ethyl acetate, washed with water andbrine, dried over sodium sulfate and evaporated to a crude product. Thiswas purified by preparative tlc (50% EtOAc/hexanes eluent) to give afterrecrystallization from ether/hexanes 15 mg of CXXX as a crystallinesolid (mp 200-201° C.).

Example 58 Compound CXXXI

[0550]

[0551] A mixture of 50 mg of CXXIX, 5 mL of isopropanol and 20 drops ofsulfuric acid was refluxed overnight. The reaction mixture was pouredonto water and extracted with ethyl acetate. The extracts were washedwith aqueous sodium bicarbonate, dried and evaporated to an oil. Thiswas purified by flash chromatogeaphy (25% EtOAc/hexanes eluent) to givea solid that was recrystallized from ether/hexanes to give 24 mg ofCXXXI as a crystalline solid imp 153-154° C.).

Example 59

[0552] Compound CXXXIX

[0553] To a −78° C. solution of 719 mg of tributyl (isopropoxymethyl)tinand 0.4 ml of TMEDA in 4 mL of anhydrous THF was added 0.53 ml of 2.5Mbutyllithium in hexane. After 5 min, 100 mg of CV was added in a singleportion, and the stirred suspension was allowed to warm to −20° C. over35 min. The cold reaction mixture was quenched by the addition ofaqueous ammonium chloride, and then extracted with ethyl acetate. Theextracts were washed with brine, dried over sodium sulfate, andevaporated to an oily solid that was triturated with hexane to removethe tetraalkyltin byproduct. The crude solid was purified by flashchromatography (50% EtOAc/hexanes eluent) and then preparative tlc (67%EtOAc/hexanes eluent) to give after crystallization (ether/hexanes) 13mg of CXXXIX (mp 163-164° C.)

Example 60 Compound CXL

[0554]

[0555] To a 0° C. solution of XXV (R=n-butyl) in 4 mL of dryacetonitrile was added 60 mg of N-chlorosuccinimide. After 30 min thecooling bath was removed and the reaction mixture was stirred at ambienttemperature for 1.5 h. The mixture was diluted with ethyl acetate,washed twice with water and once with brine, dried over sodium sulfateand evaporated to give after crystallization from ether/ hexanes 48 mgof CXL as pure crystals (mp 234-236° C.).

Example 61 Compound CXLIII

[0556]

[0557] Step A: Preparation of CXLII.

[0558] A mixture of 200 mg of XXIII, and 105 mg of N-chlorosuccinimidein 20 ml of acetic acid was refluxed for 1 h. The solvent was evaporatedand the crude reaction product was dissolved in ethyl acetate and thissolution was washed twice with water and once with brine, dried oversodium sulfate and evaporated to give the intermediate solid additionproduct CXLI. This material was heated neat at 130-140° C. for 3 h togive 125 mg of CXLII as bright yellow crystals.

[0559] Step B: Preparation of CXLIII.

[0560] To a −78° C. mixture of 100 mg of CXLII in 10 mL of dry THF and 1mL of TMEDA was added dropwise 1.5 mL of 1.6 M butyllithium and themixture was stirred 30 min at −78° C. The cold reaction mixture wasquenched by the addition of aqueous citric acid, and then extracted withethyl acetate. The extracts were washed with water and brine, dried oversodium sulfate, and evaporated to crude product that was purified byflash chromatography (25-50% EtOAc/hexanes eluent) to give aftercrystallization from ether 11 mg of CXLIII as a crystalline solid (mp252-255° C).

Example 62 CXLIX

[0561]

[0562] Step A: preparation of CXLIV

[0563] To a 0° C. suspension of XX (700 mg, 1.7 mmol) in DMF (70 mL) wasadded NaCN (167 mg, 3.4 mmol). After stirring overnight, the reactionwas diluted with EtOAc and washed with salturated NaHCO₃, water andbrine. Concentration gave a brown solid (CXLIV, 800 mg).

[0564] Step B: preparation of CXLV

[0565] To −78° C. solution of CXLIV (800 mg) in dichloromethane (35 mL)was added a solution of 1 M DIBAL in dichloromethane (3.8 mL). Thereaction was quenched with 3 N HCl and diluted with EtOAc, washed with 3N HCl (3×), saturated NaHCO₃ and brine. The organic phase was dried overNa₂SO₄ and concentrated to a pale orange solid (CXLV, 750 mg).

[0566] Step C: preparation of CXLVI

[0567] A suspension of CXLV (750 mg) and NaBH₄ (140 mg) in MeOH (7 mL)was stirred for 15 min. The reaction was diluted with EtOAc, washed withwater (2×) and brine. The organic phase was dried over Na₂SO₄ andconcentrated to a pale orange solid which was triturated with ether togive CXLVI (570 mg).

[0568] Step D: preparation of CXLVII

[0569] To a 0° C. solution of CXLVI (330 mg) and DIEA (0.95 mL) in DMF(4 mL) was added MsCl (0.21 mL). The reaction was diluted with EtOAc,washed with dilute HCl (2×), salturated NaHCO₃ and brine. The organicphase was dried over Na₂SO₄ and concentrated to an orange thick oil(CXLVII, 480 mg).

[0570] Step E: preparation of CXLVIII

[0571] A solution of CXLVII (415 mg) in EtOH (100 mL) and 21% NaOEt inEtOH (150 mL) was stirred for 3 days. The reaction was diluted withEtOAc, washed with water (2×) and brine. The organic phase wasconcentrated and chromatographied to give an orange oil (CXLVIII, 73mg).

[0572] Step F: preparation of CXLIX

[0573] A solution of CXLVIII (70 mg) in EtOH (8 mL) and concentrated HCl(4 mL) was refluxed for 1 h. The reaction was diluted with EtOAc andneutralized with KOH, and washed with brine. The organic phase was driedover Na₂SO₄ and triturated with ether to give a brown solid (CXLIX 46mg), M.P. 240-245° C.

Example 61a

[0574]

[0575] Step A:

[0576] To a 0° C. suspension of XVI (1.1 g, 4.2 mmol) in THF (10 mL) wasadded a solution of 1.4 M MeLi in ether (6.6 mL, 9.3 mmol). Afterstirred for 10 min., the reaction was quenched with sat. NH₄Cl.Partitioned between EtOAc and sat. NH₄Cl and washed with brine. Theorganic phase was dried over Na₂SO₄ and concentrated to give 0.97 g ofyellow solid (CL, 88% yield).

[0577] StepB:

[0578] To a −78° C. solution of CL (100 mg, 0.39 mmol) in THF (1 mL) andTMEDA (0.1 mL) was added a solution of 1.6 M BuLi in hexanes (0.73 mL,1.16 mmol). The reaction was allowed to warm to 0° C., then quenchedwith sat. NH₄Cl. Partitioned between EtOAc and sat. NH₄Cl and washedwith brine. The organic phase was dried over Na₂SO₄ and concentrated.Flash chromatography (15% EtOAc/hexanes) gave 41 mg of an orange oil.

[0579] Demethylation: The oil (41 mg) was refluxed in conc. HCl (1 Ml)and EtOH (3 ml) FOR 1 h. The reaction was diluted with EtOAc, washedwith 10% NaOH, then water and brine. The organic phase was dried overNa₂SO₄ and concentrated. Crystallization from ether/hexanes gave 24 mgof brown solid (CLII).

Example 62a

[0580] The compound CLI was prepared as described from CLII.

[0581] Step A:

[0582] CLIII was prepared as described in Compound CL.

[0583] Step B:

[0584] A suspension of CLIII (408 mg, 1.36 mnol) and NaCN (124 mg, 2.04mmol) in DMF (4.5 mL) and TFA (0.11 mL,1.36 mmol) was stirred overnight.The reaction was diluted with EtOAc, washed with saturated NaHCO₃, thenwater and brine. The organic phase was dried over Na₂SO₄ andconcentrated. Flash chromatography (25% EtOAc/hexanes) gave 390 mg ofsolid (CLIV, 88% yield).

[0585] Step C:

[0586] CLIV was treated with HCl to give CLV as described in CompoundCLII.

Example 64

[0587] The compound CLIV (200 mg) was treated with DIBAL in methylenechloride at −78° C. to give an orange oil (187 mg, 93%) after 3 NHCl/EtOAc workup. The aldehyde was reduced to the alcohol with NaBH₄ inMeOH in nearly quantitative yield. The demethylation was as described inCompound CLII to give CLVI.

Example 65

[0588]

[0589] Step A:

[0590] 2,3-Dichloropyridine (9.717 g, 65.00 mmol) was treated with 25 wt% sodium methoxide in methanol (74.4 mL, 325.0 mmol). The resultingmilky suspension was heated to reflux for 15 h 30 min. The reactionmixture was cooled to rt and quenched with H₂O (150 mL), extracted withEtOAc (2 X). The combined organic phases were washed with brine, driedover MgSO₄, filtered and concentrated in vacuo. The residue wasdistilled under vacuo (65° C./8 mmHg) to give CLVII (8.354 g, 90% yield)as a colorless oil.

[0591] Step B:

[0592] To a stirred solution of CLVII (2.152 g, 15.0 mmol) in anhydrousTHF (20 mL) at −78° C. was slowly added LDA (2M solution in THF, 7.50mL, 15.0 mmol). After 1 hour at −78° C., CH₃CF₂COOEt (1.30 mL, 10.0mmol) was added dropwise. The reaction mixture was stirred at −78° C.for 2 h and then at 0° C. for one more hour. The reaction was quenchedwith saturated aqueous NH₄Cl solution and extracted with EtOAc (3 X).The combined organic phases were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (Hexane:Et₂O=9:1) to give CLVIII (1.864 g, 79% yield).

[0593] Step C:

[0594] To a stirred solution of 4-chloroaniline (13.47 g, 104.5 mmol) inanhydrous CH₂Cl₂ (300ml) at 0° C. was added triethylamine (21.85 mL,156.8 mmol) and pivaloyl chloride (15.60 mL, 125.4 mmol). The reactionmixture was stirred at rt for 1.5 h. The reaction was quenched with 1NHCl (150 mL) and extracted with CH₂Cl₂ (2 X). The combined organiclayers were washed with saturated aqueous NaHCO₃, brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The off-white solidwas suspended in hexanes (100 mL) and stirred at rt for 10 min. Theproduct was filtered and dried under vacuum to give CLIX (21.687 g, 98%yield) as a white solid, m.p. 149-150° C.

[0595] Step D:

[0596] To a stirred solution of 4-fluoroaniline (10.0 mL, 0.104 mol) inanhydrous CH₂Cl₂ (300 ml) at 0° C. was added triethylamine (21.9 mL,0.157 mmol) and pivaloyl chloride (15.6 mL, 0.125 mmol). After 3 h atrt, the reaction mixture was quenched with 1N HCl (250 mL) and extractedwith CH₂Cl₂ (3×200mL). The combined organic layers were washed withsaturated aqueous NaHCO3, brine, dried over anhydrous MgSO₄, filteredand concentrated in vacuo to give white needle crystal. The crystal wasrinsed with hexane and dried under vacuum to give CLX (19.4 g, 96%yield) as a white crystal.

[0597] Step E:

[0598] To a stirred solution of 4-Chloro-N-pivaloylaniline CLIX (3.36 g,15.9 mmol) in anhydrous THF (60 mL) −78° C. was added sec-BuLi (1.3 M inhexane, 25 mL, 31.8 mmol) dropwise. After 2 h at 0° C., the reactionmixture was re-cooled to −78° C. and a solution of compound CLVIII (3.12g, 13.24 mmol) in THF (20 mL) was added dropwise. The reaction mixturewas warmed to −20° C. to −30° C. and stirred for 2.5 h. The reaction wasquenched with saturated aqueous NH₄Cl solution and extracted with ethylacetate. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. Flash chromatography purificationgave CLXI (4.14 g, 70% yield) as a white solid.

[0599] Step F:

[0600] To a stirred solution of 4-fluoro-N-pivaloylaniline CLX (730 mg,3.74 mmol) in anhydrous THF (15mL) at -78° C. was added sec-BuLi (1.3Min Hexane, 5.75 mL, 7.48 mmol). After 1.5 h at 0° C., the reactionmixture was re-cooled to −78° C. and a solution of compound CLVIII (734mg, 3.10 mmol) in THF (3 mL) was added dropwise. The reaction mixturewas stirred at −78° C. for 1 h and then stirred between −20° C. and −30°for 1 h. The reaction was quenched with saturated aqueous NH₄Cl solutionand extracted with ethyl acetate (3×60 mL). The combined organic phaseswere washed with brine, dried over MgSO₄, filtered and concentrated invacuo. Flash chromatography purification gave CLXII (1.864 g, 67% yield)as a white solid.

[0601] Step G:

[0602] To a stirred solution of CLXI (4.134 g, 9.24 mmol) in anhydrousDMF (100 mL) at 0° C. was added NaH (60% in mineral oil, 450 mg, 11.25mmol) in 3 portions. The resulting suspension was stirred for lOmin andMeI (750 μg, 11.8 mmol) was added. After 2 h at rt, another portion ofNaH (25 mg, 0.625 mmol) and MeI (0.55 mmol) was added. After stirringfor 45minutes at rt, the reaction was quenched with saturated aqueousNH4Cl and extracted with ethyl acetate (2 X). The combined organicphases were washed with brine, dried over MgSO₄, filtered andconcentrated to give a white solid. The solid was triturated withhexane, filtered to give CLXIII (4.156 g, 98% yield) as a white solid.

[0603] Step H:

[0604] To a stirred solution of CLXII (1.846 g, 4.3 mmol) in anhydrousDMF (25mL) at 0° C. was added NaH (60% in mineral oil, 225 mg, 5.57mmol). The resulting suspension was stirred for 10 min and MeI (410 μL,6.45 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hand then at rt for another 1.5 h. The reaction was quenched with water(50 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic phases were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by column chromatography(Hexane:EtOAc=6:1) to give CLXIV (1.72 g, 99% yield) as a pale solid.

[0605] Step J:

[0606] To a stirred solution of CLXIII (4.156 g, 9 mmol) in ethanol (20mL) was added HBr (48% aqueous solution, 40 mL 360 mmol). The reactionmixture was heated at 100° C. for 48 h. The mixture was cooled to 0° C.and neutralized carefully with concentrated NaOH (50% wt) and saturatedaqueous Na₂CO₃ to pH 8-9, extracted with ethyl acetate. The organicphase was washed with brine, dried over MgSO₄, filtered and concentratedto give a light yellow solid. The solid was triturated with ether andfiltered to give CLXV (3.2 g, 98% yield).

[0607] Step K:

[0608] To a stirred solution of CLXIV(445 mg, 1.0 mmol) in ethanol (6mL) was added HBr (48% solution in H₂O, 3.4 mL, 30 mmol). The reactionmixture was heated at 100° C. for 48 h. The mixture was cooled to 0° C.and neutralized carefully with concentrated NaOH (50% wt) and saturatedaqueous Na₂CO₃ to pH 8-9, extracted with ethyl acetate (3 X). Thecombined organic phases were washed with brine, dried over MgSO₄,filtered and concentrated to give a white solid. The solid was rinsedwith ether and filter to give CLXVI (307 mg, 88% yield).

[0609] Step L:

[0610] To a stirred solution of CLXV (187 mg, 0.515 mmol) in dry DMF(25ml) was added K₂CO₃ (142 mg, 1.03 mmol). The reaction mixture washeated to reflux for 3 h. The reaction mixture was cooled to rt andquenched with H₂O (20 mL). The solid was filtered, washed with water andhexane, dried under vacuum to give CLXVII (150 mg, 99% yield) as a brownsolid.

[0611] Step M:

[0612] A suspension of CLXVI (690 mg, 2 mmol) in diphenyl ether (5 mL)was heated at 225° C. for 1.5 h. The reaction mixture was cooled to rtand diluted with ether. The black solid precipitated and was filtered togive CLXVIII (527 mg, 95%) as the crude product.

[0613] Step N:

[0614] To a stirred suspension of compound CLXIX (87 mg, 0.295 mmol) inanhydrous THF (5 mL) at −78° C. was slowly added n-BuLi (2.5 M inhexane, 1.18 mL, 2.95 mmol). The resulting brown solution was stirred at−78° C. for 3 h 30 min. The reaction was quenched with water (20 mL) andextracted with ethyl acetate (2 X). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by column chromatography (EtOAc:Hexane =3:2) togive CLXXI (53 mg, 51% yield) as a pale yellow solid, m.p. 120-122° C.,MS (ES): (M+H)⁺=353.3, (M-H)⁻=351.2.

Example 66

[0615] Step O:

[0616] To a stirred suspension of compound CLXX (95 mg, crude) inanhydrous THF (6 mL) at −78° C. was slowly added n-BuLi (1.6 M inhexane, 1.5 mL, 2.4 mmol). The reaction mixture was stirred at −78° C.for 30 min. The reaction was quenched with saturated aqueous NH₄Cl andextracted with ethyl acetate (3×50 mL). The combined ethyl acetatelayers were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash column(CH₂Cl₂:MeOH=100:4) to give CLXXII (16 mg, 14% yield) as a white solid,m.p. 267-270° C., MS (ES): (M+H)⁺=337.3, (M-H)⁻=335.3.

Example 67

[0617] Step P:

[0618] A degassed mixture of CLXXI (105 mg, 0.298 mmol), Zn(CN)₂ (72 mg,0.595 mmol),{Dichloro[1,1′-Bis(diphenylphosphino)ferrocene]Palladium(II)dichloromethane adduct} (98 mg, 0.12 mmol) and Zn powder (24 mg, 0.36mmol) in 1-methyl-2-pyrrolidinone (3 mL) was heated at 150° C. for 48h.The reaction mixture was cooled to rt, diluted with ethyl acetate,filtered through a pad of Celite and washed with ethyl acetate. Thefiltrate was washed with 2N NH₄OH, brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash column chromatography(EtOAc:Hexane:AcCN=7:20:3) to give CLXXIII (28 mg, 27% yield) as a lightyellow solid. m.p. 132.2-134.7° C., MS (ES): (M+H)⁺=344.3, (M-H)⁻=342.3.

Example 68

[0619]

[0620] Step A:

[0621] To a solution of compound CLXIX (694 mg, 2.355 mmol) in anhydrousDMF (15 mL) was added NaCN (258 mg, 5.0 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction mixture was filteredthrough a pad of Celite and washed with CH₂Cl₂. 100 mL of H₂O was addedto the filtrate and the mixture was extracted with CH₂Cl₂ (3×150 mL).The combined organic layers were washed with saturated aqueous NaHCO₃,brine and dried over MgSO₄, filtered and concentrated. The residue waspurified by column chromatography (CH₂Cl₂:MeOH=100:4) to give CLXXIV(520 mg, 68% yield).

[0622] Step B:

[0623] To a stirred solution of CLXXIV (518 mg, 1.61 mmol) in anhydrousCH₂Cl₂ (20 mL) at −78° C. was added slowly DIBAL (1 M in CH₂Cl₂, 2.0 mL,2.0 mmol). After 3 h at −50° C., another portion of 1 M (2.6 mL, 2.6mmol) was added. The reaction mixture was stirred at at −50° C. for 2h.The reaction was quenched with 1 N HCl (20 mL) and extracted with ethylacetate (3×150 mL). The combined organic layers were washed by saturatedaqueous NaHCO₃, brine and dried over MgSO₄, filtered and concentrated.The residue was crystallized in a small volume of ether to give CLXXV(364 mg, 70% yield) as a white crystal (70%).

[0624] Step C:

[0625] A solution of CLXXV (165 mg, 0.5 mmol), CH(OEt)₃ (5 mL, 29.5mmol) and p-toluensulfonic acid monohydrate (245 mg, 1.29 mmol) wasstirred at room temperature for 18h. The reaction mixture wasneutralized by 1 N NaOH and extracted with ethyl acetate. The organiclayer was washed with brine and dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatography(EtOAc:Hexane=2:1) to give CLXXVI (131 mg, 66% yield).

[0626] Step D:

[0627] To a stirred solution of compound CLXXVI (130 mg, 0.326 mmol) inTFA (2.5mL) /TFAA (0.08 ml) at 0° C. was added BH₃.Me₂S (10.0-10.2 M,150 μL, 1.515 mmol) dropwise. After stirring at rt for 2 h, anotherportion of BH₃·Me₂S (10.0-10.2M, 120 μL, 1.21 mmol) was added dropwise.After stirring at room temperature for another 2 h, the solvent TFA wasremoved in vacuo. The residue was neutralized with 1 N NaOH andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with saturated aqueous NaHCO₃, brine and dried over MgSO₄,filtered and concentrated. The residue was dissolved in 3 mL of 4 N HClin Dioxane and 3 mL of MeOH. The mixture was stirred at room temperaturefor 2 h to hydrolyze the formed B(OOCCF₃)₃. The mixture was thenconcentrated and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with 1 N NaOH, brine, dried over MgSO₄,filtered and concentrated. The residue was purified by columnchromatography (CH₂Cl₂:MeOH 100:4) to give CLXXVII (64 mg, 55% yield).m.p. 265-267° C., MS (ES): (M+H)⁺=355.3, (M-H)⁻=353.3.

[0628] Examples 101, 111, 112 and 113 were prepared using the proceduredescribed in Example 4.

Example 110

[0629]

[0630] Step A:

[0631] 0.37 ml of anhydrous acetonitrile was dissolved in 10 ml ofanhydrous THF, and cooled to −78° C. 4.0 ml of 2M lithiumdiisopropylamide in heptane/THF/ethylbenzene was added. The mixture wasallowed to stir at −78° C. for 20 minutes. Aromatic intermediate IX (500mg) was added in one portion. The mixture was stirred an additional 1hour at −78° C., and quenched with saturated aqueous ammonium chloride.Partitioning between EtOAc/water, drying over magnesium sulfate andconcentration yielded a brown oil. Purification by flash chromatography(60% EtOAc/hexane, silica gel) gave 400 mg of CLXXVIII as a yellowsolid. (70% yield)

[0632] Step B:

[0633] 820 mg of nitrile CLXXVIII was dissolved in 6 ml ofdichloromethane and cooled to −78° C. 7.3 ml (3 equivalents) of 1Mdiisobutylaluminum hydride in dichloromethane was added. The mixture waswarmed to −30° C. over 2 hours. The mixture was quenched with 3N HCl andextracted with EtOAc. Drying over sodium sulfate and concentrationyielded a yellow oil which after flash chromatography (60% EtOAc/hexane,silica gel) gave aldehyde CLXXIX. (605 mg, 73% yield)

[0634] Step C:

[0635] 240 mg of aldehyde CLXXIX, 0.061 ml of cyclopropylamine (1.2equivalents), 314 mg of sodium triacetoxyborohydride (2.0 equivalents)and 0.042 ml (1.0 equivalent) of acetic acid were combined in a flaskand stirred 1 hour at 25° C. The mixture was partitioned between EtOAc/saturated aqueous sodium bicarbonate, dried over magnesium sulfate andconcentrated. Flash chromatography (10% methanol/ dichloromethane,silica gel) gave 145 mg of CLXXX as a yellow solid. (53% yield)

[0636] Examples 104-106, 108-109 and 119-120 were prepared using theprocedure described in example 110.

Example 122

[0637]

[0638] Step A:

[0639] Aldehyde CLXXXI (83 mg), trimethyl orthoformate (1 ml), andp-toluenesulfonic acid hydrate (91 mg, 2 equivalents), were dissolved in2 ml methanol and ref luxed for 2 hours. The solution was cooled andconcentrated to a yellow oil. Purification by flash chromatography (20%EtOAc/hexane, silica gel) yielded acetal CLXXXII as a clear oil, 87 mg.(93% yield)

[0640] Step B:

[0641] Compound CLXXXII was dissolved in 1 ml dichloromethane. I mltrifluoroacetic acid and 0.393 ml triethylsilane (10 equivalents) wereadded. The solution was stirred 1 hour at 25° C., then concentrated to ayellow oil. Purification by preparative TLC (20% EtOAc/hexane, silicagel) yielded compound CLXXXIII as a clear oil, 29 mg. (33% yield)

[0642] Step C:

[0643] Compound CLXXXIII (29 mg) was dissolved in 2 ml methanol. 0.5 mlconcentrated HCl was added. The solution was heated to reflux for 1 hr,then cooled. It was partitioned between EtOAc/ saturated aqueous sodiumbicarbonate, washed once with water, dried over magnesium sulfate, andconcentrated to a brown oil. Purification by preparative TLC (10%methanol/dichloromethane, silica gel) gave 12 mg of compound CLXXXIIIaas a brown solid. (43% yield)

[0644] Examples 107 and 118 were prepared using the procedure describedin example 122.

[0645] Examples 124, 126, 127-130, and 135 were prepared using theprocedure described in example 30.

[0646] Example 123 was prepared using the procedure described in example28.

Example 115

[0647]

[0648] Step A:

[0649] Compound CLXXXIV (75 mg), potassium carbonate (249 mg, 10equivalents), and pyrazole (122 mg, 10 equivalents) were dissolved in 1ml anhydrous DMF and heated to 100° C. 18 hours The mixture was cooledand partitioned between EtOAc/water, washed once with water and driedover magnesium sulfate. Purification by preparative TLC (30%EtOAc/hexane, silica gel) gave compound CLXXXV as a yellow oil. (36 mg,51% yield)

[0650] Step B:

[0651] Compound CLXXXV (36 mg) was dissolved in 2 ml methanol. 1 mlconcentrated HCl was added, and the solution was heated to reflux for 1hr, then cooled. It was partitioned between EtOAc/ saturated aqueoussodium bicarbonate, washed once with water, dried over magnesiumsulfate, and concentrated to a yellow oil. Purification by preparativeTLC (5% methanol/dichloromethane, silica gel) gave 23 mg of compoundCLXXXVI as a white solid. (66% yield).

[0652] Examples 114 and 116 were prepared using the procedure describedin example 115.

[0653] Examples 125, 131, 144 and 145 were prepared using the proceduredescribed in example 28

Example 146

[0654]

[0655] 86 mg of aldehyde CLXXIX, 0.145 ml of ethylene glycol (10equivalents), and 25 mg of p-toluenesulfonic acid hydrate (0.5equivalents) were dissolved in 1.5 ml of benzene. The solution washeated to reflux 30 minutes, then cooled. It was partitioned betweenEtOAc/saturated aqueous sodium bicarbonate and washed once with water.The organic phase was reduced in volume on a rotary evaporator. Theresulting white precipitate was filtered and washed with water andtoluene to obtain pure compound CLXXXVII (70 mg, 73% yield).

[0656] Chiral HPLC separation was performed using chiral columns whichgave the (R) and (S) enantiomers in >99% EE.

[0657] The following compounds have been made using the techniquesdescribed above. TABLE 1* (I)

Ex Mass # R^(b) R² R^(3a) R⁹ Spec MP (° C.) 1 H(6-methylpyrid-2-yl)methyl F H 2 H Cyclopropylacetylenyl F H 3 Hn-Propyl F H 4 H n-Butyl F H 5 H 4-Fluorophenylmethyl F H 6 H2-Pyridylmethyl F H 7 H i-Propyl F H 8 H 3-Pyridylmethyl F H 9 H4-Pyridylmethyl F H 10 H 3-Propynyl F H 11 H 2-Pyridylethynyl F H 12 H2-(2-Pyridyl)ethyl F H 13 3- n-Propyl F H Cl 14 H 3-Propenyl F H 15 H2-Cyclopropylethyl F H 16 H Ethynyl F H 17 H 2-Ethoxyethyl F H 17a H2-chloroethyl F H 18 H n-Butyl Cl H 245-248 19 H 2-Pyridylmethyl Cl H270-275 20 H 2-Cyclopropylethyl Cl H 220-222 21 H CyclopropylacetylenylCl H 247-250 22 H N- Cl H 230-235 Cyclopropylaminomethyl 23 HHydroxymethyl Cl H 270-275 24 H 2-Pyridylmethyl Cl CH₃ 166-168 25 H2-Cyclopropylethyl Cl CH₃ 150-152 27 H n-Propoxymethyl Cl H 162-165 28 Hi-Propoxymethyl Cl H 185-190 29 H Methoxyethyl Cl H 268-271 29a Hdiisopropoxymethyl Cl H 30 H i-Propylaminomethyl Cl H 235-240 31 HN-Methyl-i- Cl H 105-110 propylaminomethyl 32 H CyclopropylaminomethylCl H 242-245 33 H n-Propylaminomethyl Cl H 243-245 34 HCyclobutylaminomethyl Cl H 250-254 35 H i-Butylaminomethyl Cl H 210-21536 H i-Propoxymethyl Cl H 195-197 37 H n-butyl CN H 38 H i-propoxymethylCN H 39 H cyclopropylthiomethyl Cl H 39a H cyclopropylsulfoxy Cl Hmethyl 40 H i-propylsulfoxymethyl Cl H 41 H t-butylsulfoxymethyl Cl H 42H methylthiomethyl Cl H 43 H ethylthiomethyl Cl H 44 Hi-propylthiomethyl Cl H 45 H i-propylthiomethyl F H 46 Ht-butylthiomethyl Cl H 47 H cyclopropylmethoxy Cl H methyl 48 Hcyclobutoxymethyl Cl H 49 H cyclobutoxymethyl F H 50 Hcyclopropylmethoxy F H methyl 51 3- i-propoxymethyl Cl H CH₃ 52 3-n-butyl Cl H CH₃ 53 3- n-butyl CN H CH₃ 60 3- n-butyl Cl H Cl 61 4-n-butyl Cl H Cl 62 H ethoxyethyl Cl H 240-245 100 H allyl F H 101 H2-methyl-1-propenyl F H 337.1 102 H 1-propynyl F H 103 H cyanomethyl F H104 H 2-(ethylamino)ethyl F H 356.4 105 H 2-(dimethylamino)ethyl F H356.4 106 H 2-(methylamino)ethyl F H 340.3 107 H 2-ethoxyethyl F H 355.3108 H 2-(i-propylamino)ethyl F H 370.4 109 H 2-(diethylamino)ethyl F H384.4 110 H 2-(cyclopropylamino) F H 366.3 ethyl 111 H pentyl F H 353.4112 H i-butyl F H 339.4 113 H vinyl F H 309.3 114 H imidazolylethyl F H379.4 115 H pyrazolylethyl F H 379.3 116 H 1,2,4-triazolylethyl F H378.3 117 H i-propylaminomethyl F H 356.4 118 H 2-(i-propoxy)ethyl F H369.3 119 H 2-(methylethylamino) F H 370.4 ethyl 120 H 2-(i- F H 384.4propylmethylamino) ethyl 121 H 2-(pyrrolidinyl)ethyl F H 382.4 122 H2-(methoxy)ethyl F H 341.3 123 H i-propoxymethyl F H 357.1 124 H3-pentanylaminomethyl F H 384.4 125 H dimethoxymethyl F H 357.3 126 Hi-butylaminomethyl F H 370.4 127 H cyclopropylmethyl F H 368.3aminomethyl 128 H allylaminomethyl F H 354.3 129 H (R)-sec- F H 370.4butylaminomethyl 130 H (S)-sec- F H 370.3 butylaminomethyl 131 Hdiethoxymethyl F H 387.3 132 3- propyl F H Cl 133 H butyl F Me 353.3 134H 2-(i-propoxy)ethyl F Me 383.3 135 H i-propylaminomethyl F Me 370.4 136H i-propoxymethyl F Me 371.1 137 H 2-ethoxyethyl F Me 371.1 138 Hsec-butylaminomethyl F Me 384.4 139 H cyclopentylaminomethyl F H 382.1140 H cyclobutylaminomethyl F H 368.3 141 H dimethylaminomethyl F H342.3 142 H pyrrolidinylmethyl F H 368.3 143 H cyclopropylaminomethyl FH 354.3 144 H 2-(dimethoxy)ethyl F H 371.2 145 H 2-(diethoxy)ethyl F H399.3 146 H 2-(1,3- F H 369.2 dioxolanyl)methyl 147 H 2-(methoxy)ethyl FCH₃ 357.1

[0658] TABLE 1A*

Ex # R^(3a) R¹ R² MP (° C.) 61a Cl CH₃ butyl 177-179 62a Cl CH₃i-propoxymethyl 63 Cl CN butyl 182-185 64 Cl CH₂OH butyl 260-265 64a ClCHF₂ butyl 198-200 64b Cl CHF₂ i-propoxymethyl 138-142 65 Cl CF₂CH₃n-butyl 66 F CF₂CH₃ n-Butyl 67 CN CF₂CH₃ n-butyl 68 Cl CF₂CH₃ethoxymethyl

[0659] The following compounds were prepared from the racemic mixturesusing the procedure described above. TABLE 1B

Ex # R^(3a) R⁹ R² R^(b) MP (° C.) 200 F H 2-pyridylmethyl H 201 F Hbutyl H 202 Cl H 2-pyridylmethyl H 203 Cl H 2-cyclopropylethyl H 204 F H2-(6-methyl)pyridylmethyl H 205 F Me butyl H 206 Cl H i-propoxymethyl H207 Cl H i-propylaminomethyl H 208 Cl H cyclopropylaminomethyl H 209 ClMe i-propoxymethyl H 210 F H i-propoxymethyl H 211 Cl Hi-propylmethylaminomethyl H 212 Cl H 2-methoxyethyl H 213 Cl Hcyclobutoxymethyl H 214 Cl H ethoxymethyl H 215 CN H i-propoxymethyl H216 Cl H i-propoxymethy Me

[0660] The following table contains representative examples of thepresent invention. Each entry in each table is intended to be pairedwith the formula at the start of the table. For example, in Table 2, thecompound is intended to be paired with one of 1a-11a, one of 1b-4b, oneof 1c-4c, one of 1d-5d and one of 1-60e. TABLE 2 # R¹  1a CF₃  2a CHF₂ 3a CH₃  4a cyclopropyl  5a CF₂CF₃  6a methyl  7a ethyl  8a propyl  9abutyl 10a CN 11a hydroxymethyl R^(3a)  1b H  2b chloro  3b fluoro  4bCH₃ R^(b)  1c 3-chloro  2c 4-methyl  3c 4-chloro  4c H R⁹  1d H  2dmethyl  3d ethyl  4d propyl  5d butyl R²  1e (6-methylpyrid-2-yl)methyl 2e Cyclopropylacetylenyl  3e n-Propyl  4e n-Butyl  5e4-Fluorophenylmethyl  6e 2-Pyridylmethyl  7e i-Propyl  8e3-Pyridylmethyl  9e 4-Pyridylmethyl 10e 3-Propynyl 11e 2-Pyridylethynyl12e 2-(2-Pyridyl)ethyl 13e n-Propyl 14e 3-Propenyl 15e2-Cyclopropylethyl 16e Ethynyl 17e 2-Ethoxyethyl 18e 2-chloroethyl 19eN-Cyclopropylaminomethyl 20e Hydroxymethyl 21e n-Propoxymethyl 22ei-Propoxymethyl 23e Methoxyethyl 24e diisopropoxymethyl 25ePropylaminomethyl 26e N-Methyl-i-propylaminomethyl 27en-Propylaminomethyl 28e Cyclobutylaminomethyl 29e i-Butylaminomethyl 30ecyclopropylthiomethyl 31e i-propylsulfoxymethyl 32e t-butylsulfoxymethyl33e methylthiomethyl 34e ethylthiomethyl 35e i-propylthiomethyl 36ecyclopropylmethoxymethyl 37e cyclobutoxymethyl 38e cyanomethyl 39e2-(ethylamino)ethyl 40e 2-(dimethylamino)ethyl 41e 2-(methylamino)ethyl42e 2-i-propylamino)ethyl 43e 2-(cyclopropylamino)ethyl 44e pentyl 45evinyl 46e imidazolylethyl 47e pyrazolylethyl 48e 1,2,4-triazolylethyl49e 2-(methylethylamino)ethyl 50e 2-(i-propylethylamino)ethyl 51e2-(pyrrolidinyl)ethyl 52e 3-pentanylaminomethyl 53e dimethoxymethyl 54ei-butylaminomethyl 55e cyclopropylmethyl aminomethyl 56eallylaminomethyl 57e (R)-sec-butylaminomethyl 58e(S)-sec-butylaminomethyl 59e 1,3-dioxolanylmethyl 60e 1,3-dioxanylmethyl

UTILITY

[0661] The compounds of this invention possess reverse transcriptaseinhibitory activity and HIV inhibitory efficacy. The compounds offormula (I) possess HIV reverse transcriptase inhibitory activity andare therefore useful as antiviral agents for the treatment of HIVinfection and associated diseases. The compounds of formula (I) possessHIV reverse transcriptase inhibitory activity and are effective asinhibitors of HIV growth. The ability of the compounds of the presentinvention to inhibit viral growth or infectivity is demonstrated instandard assay of viral growth or infectivity, for example, using theassay described below.

[0662] The compounds of formula (I) of the present invention are alsouseful for the inhibition of HIV in an ex vivo sample containing HIV orexpected to be exposed to HIV. Thus, the compounds of the presentinvention may be used to inhibit HIV present in a body fluid sample (forexample, a serum or semen sample) that contains or is suspected tocontain or be exposed to HIV.

[0663] The compounds provided by this invention are also useful asstandard or reference compounds for use in tests or assays fordetermining the ability of an agent to inhibit viral replication and/orHIV reverse transcriptase, for example in a pharmaceutical researchprogram. Thus, the compounds of the present invention may be used as acontrol or reference compound in such assays and as a quality controlstandard. The compounds of the present invention may be provided in acommercial kit or container for use as such standard or referencecompound.

[0664] Since the compounds of the present invention exhibit specificityfor HIV reverse transcriptase, the compounds of the present inventionmay also be useful as diagnostic reagents in diagnostic assays for thedetection of HIV reverse transcriptase. Thus, inhibition of the reversetranscriptase activity in an assay (such as the assays described herein)by a compound of the present invention would be indicative of thepresence of HIV reverse transcriptase and HIV virus.

[0665] As used herein “μg” denotes microgram, “mg” denotes milligram,“g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “mM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar and “nm” denotes nanometer.“Sigma” stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

[0666] Compounds tested in the assay described below are considered tobe active if they exhibit a K_(i) of ≦10 μM. Preferred compounds of thepresent invention have K_(i)'s of ≦1 μM. More preferred compounds of thepresent invention have K_(i)'s of ≦0.1 μM. Even more preferred compoundsof the present invention have K_(i)'s of ≦0.01 μM. Still more preferredcompounds of the present invention have K_(i)'s of ≦0.001 μM.

[0667] Using the methodology described below, a number of compounds ofthe present invention were found to exhibit a K_(i) of ≦10 μM, therebyconfirming the utility of the compounds of the present invention aseffective HIV reverse transcriptase inhibitors.

HIV RNA Assay

[0668] DNA Plasmids and in vitro RNA transcripts:

[0669] Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp113-1816) cloned into PTZ 19R was prepared according toErickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5,577. The plasmid was linearized with Bam HI prior to the generation ofin vitro RNA transcripts using the Riboprobe Gemini system II kit(Promega) with T7 RNA polymerase. Synthesized RNA was purified bytreatment with RNase free DNAse (Promega), phenol-chloroform extraction,and ethanol precipitation. RNA transcripts were dissolved in water, andstored at −70° C. The concentration of RNA was determined from the A₂₆₀.

[0670] Probes:

[0671] Biotinylated capture probes were purified by HPLC after synthesison an Applied Biosystems (Foster City, Calif.) DNA synthesizer byaddition of biotin to the 5′ terminal end of the oligonucleotide, usingthe biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30,6287. The gag biotinylated capture probe(5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3′) was complementary to nucleotides889-912 of HXB2 and the pol biotinylated capture probe (5′-biotin-CCCTATCATTTTTGGTTTCCAT 3′) was complementary to nucleotides 2374-2395of HXB2. Alkaline phosphatase conjugated oligonucleotides used asreporter probes were prepared by Syngene (San Diego, Calif.). The polreporter probe (5′ CTGTCTTACTTTGATAAAACCTC 3′) was complementary tonucleotides 2403-2425 of HXB2. The gag reporter probe (5′CCCAGTATTTGTCTACAGCCTTCT 3′) was complementary to nucleotides 950-973 ofHXB2. All nucleotide positions are those of the GenBank Genetic SequenceData Bank as accessed through the Genetics Computer Group SequenceAnalysis Software Package (Devereau Nucleic Acids Research 1984, 12,387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 MNaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. Thebiotinylated capture probes were prepared as 100 μM stocks in water.

[0672] Strentavidin coated plates:

[0673] Streptavidin coated plates were obtained from DuPontBiotechnology Systems (Boston, Mass.).

[0674] Cells and virus stocks:

[0675] MT-2 and MT-4 cells were maintained in RPMI 1640 supplementedwith 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells,2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF waspropagated in MT-4 cells in the same medium. Virus stocks were preparedapproximately 10 days after acute infection of MT-4 cells and stored asaliquots at −70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells(see below) Each aliquot of virus stock used for infection was thawedonly once.

[0676] For evaluation of antiviral efficacy, cells to be infected weresubcultured one day prior to infection. On the day of infection, cellswere resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulkinfections or at 2×10⁶/mL in Dulbecco's modified Eagles medium with 5%FCS for infection in microtiter plates. Virus was added and culturecontinued for 3 days at 37° C.

[0677] HIV RNA assay:

[0678] Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5M GED and capture probe to a final guanidinium isothiocyanateconcentration of 3 M and a final biotin oligonucleotide concentration of30 nM. Hybridization was carried out in sealed U bottom 96 well tissueculture plates (Nunc or Costar) for 16-20 hours at 37° C. RNAhybridization reactions were diluted three-fold with deionized water toa final guanidinium isothiocyanate concentration of 1 M and aliquots(150 μL) were transferred to streptavidin coated microtiter plateswells. Binding of capture probe and capture probe-RNA hybrid to theimmobilized streptavidin was allowed to proceed for 2 hours at roomtemperature, after which the plates were washed 6 times with DuPontELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20)A second hybridization of reporter probe to the immobilized complex ofcapture probe and hybridized target RNA was carried out in the washedstreptavidin coated well by addition of 120 pl of a hybridizationcocktail containing 4×SSC, 0.66% Triton×100, 6.66% deionized formamide,1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at37° C., the plate was again washed 6 times. Immobilized alkalinephosphatase activity was detected by addition of 100 μL of 0.2 mM4-methylumbelliferyl phosphate (MJBP, JBL Scientific) in buffer (2.5 Mdiethanolamine pH 8.9 (JBL Scientific), 10 MM MgCl2, 5 mM zinc acetatedihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). Theplates were incubated at 37° C. Fluorescence at 450 nM was measuredusing a microplate fluorometer (Dynateck) exciting at 365 nM.

[0679] Microplate based compound evaluation in HIV-1 infected MT-2cells:

[0680] Compounds to be evaluated were dissolved in DMSO and diluted inculture medium to twice the highest concentration to be tested and amaximum DMSO concentration of 2%. Further three-fold serial dilutions ofthe compound in culture medium were performed directly in U bottommicrotiter plates (Nunc). After compound dilution, MT-2 cells (50 μL)were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well).Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂incubator. For evaluation of antiviral potency, an appropriate dilutionof HIV-1 (RF) virus stock (50 μL) was added to culture wells containingcells and dilutions of the test compounds. The final volume in each wellwas 200 μL. Eight wells per plate were left uninfected with 50 μL ofmedium added in place of virus, while eight wells were infected in theabsence of any antiviral compound. For evaluation of compound toxicity,parallel plates were cultured without virus infection.

[0681] After 3 days of culture at 37° C. in a humidified chamber insidea CO₂ incubator, all but 25 μL of medium/well was removed from the HIVinfected plates. Thirty seven μL of 5 M GED containing biotinylatedcapture probe was added to the settled cells and remaining medium ineach well to a final concentration of 3 M GED and 30 nM capture probe.Hybridization of the capture probe to HIV RNA in the cell lysate wascarried out in the same microplate well used for virus culture bysealing the plate with a plate sealer (Costar), and incubating for 16-20hrs in a 37° C. incubator. Distilled water was then added to each wellto dilute the hybridization reaction three-fold and 150 μL of thisdiluted mixture was transferred to a streptavidin coated microtiterplate. HIV RNA was quantitated as described above. A standard curve,prepared by adding known amounts of pDAB 72 in vitro RNA transcript towells containing lysed uninfected cells, was run on each microtiterplate in order to determine the amount of viral RNA made during theinfection.

[0682] In order to standardize the virus inoculum used in the evaluationof compounds for antiviral activity, dilutions of virus were selectedwhich resulted in an IC₉₀ value (concentration of compound required toreduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL.IC₉₀ values of other antiviral compounds, both more and less potent thanddC, were reproducible using several stocks of HIV-1 (RF) when thisprocedure was followed. This concentration of virus corresponded to˜3×10⁵ PFU (measured by plaque assay on MT-2 cells) per assay well andtypically produced approximately 75% of the maximum viral RNA levelachievable at any virus inoculum. For the HIV RNA assay, IC₉₀ valueswere determined from the percent reduction of net signal (signal frominfected cell samples minus signal from uninfected cell samples) in theRNA assay relative to the net signal from infected, untreated cells onthe same culture plate (average of eight wells). Valid performance ofindividual infection and RNA assay tests was judged according to threecriteria. It was required that the virus infection should result in anRNA assay signal equal to or greater than the signal generated from 2 ngof pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in eachassay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateaulevel of viral RNA produced by an effective reverse transcriptaseinhibitor should be less than 10% of the level achieved in anuninhibited infection. A compound was considered active if its IC₉₀ wasfound to be less than 20 μM.

[0683] For antiviral potency tests, all manipulations in microtiterplates, following the initial addition of 2× concentrated compoundsolution to a single row of wells, were performed using a PerkinElmer/Cetus ProPette.

Protein Binding and Mutant Resistance

[0684] In order to characterize NNRTI compounds for their clinicalefficacy potential the effect of plasma proteins on antiviral potencyand measurements of antiviral potency against wild type and mutantvariants of HIV that carry amino acid changes in the known binding sitefor NNRTIs were examined. The rationale for this testing strategy is twofold:

[0685] 1. Many drugs are extensively bound to plasma proteins. Althoughthe binding affinity for most drugs for the major components of humanplasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein(AAG), is low, these major components are present in high concentrationin the blood. Only free or unbound drug is available to cross theinfected cell membrane for interaction with the target site (i.e., HIV-1reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAGon the antiviral potency in tissue culture more closely reflects thepotency of a given compound in the clinical setting. The concentrationof compound required for 90% inhibition of virus replication as measuredin a sensitive viral RNA-based detection method is designated the IC90.The fold increase in apparent IC90 for test compounds in the presence oradded levels of HSA and AAG that reflect in vivo concentrations (45mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the foldincrease, the more compound will be available to interact with thetarget site.

[0686] 2. The combination of the high rate of virus replication in theinfected individual and the poor fidelity of the viral RT results in theproduction of a quasi-species or mixtures of HIV species in the infectedindividual. These species will include a majority wild type species, butalso mutant variants of HIV and the proportion of a given mutant willreflect its relative fitness and replication rate. Because mutantvariants including mutants with changes in the amino acid sequence ofthe viral RT likely pre-exist in the infected individual'squasi-species, the overall potency observed in the clinical setting willreflect the ability of a drug to inhibit not only wild type HIV-1, butmutant variants as well. We thus have constructed, in a known geneticbackground, mutant variants of HIV-1 that carry amino acid substitutionsat positions thought to be involved in NNRTI binding, and measured theability of test compounds to inhibit replication of these mutantviruses. The concentration of compound required for 90% inhibition ofvirus replication as measured in a sensitive viral RNA-based detectionmethod is designated the IC90. It is desirable to have a compound whichhas high activity against a variety of mutants.

Dosage and Formulation

[0687] The antiviral compounds of this invention can be administered astreatment for viral infections by any means that produces contact of theactive agent with the agent's site of action, i.e., the viral reversetranscriptase, in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butpreferably are administered with a pharmaceutical carrier selected onthe basis of the chosen route of administration and standardpharmaceutical practice.

[0688] The dosage administered will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration; the age,health and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;and the effect desired. A daily dosage of active ingredient can beexpected to be about 0.001 to about 1000 milligrams per kilogram of bodyweight, with the preferred dose being about 0.1 to about 30 mg/kg.

[0689] Dosage forms of compositions suitable for administration containfrom about 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions the active ingredient will ordinarily bepresent in an amount of about 0.5-95% by weight based on the totalweight of the composition. The active ingredient can be administeredorally in solid dosage forms, such as capsules, tablets and powders, orin liquid dosage forms, such as elixirs, syrups and suspensions. It canalso be administered parenterally, in sterile liquid dosage forms.

[0690] Gelatin capsules contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

[0691] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts, and sodium EDTA. In addition, parenteral solutions cancontain preservatives, such as benzalkonium chloride, methyl- orpropyl-paraben and chlorobutanol. Suitable pharmaceutical carriers aredescribed in Remington's Pharnaceutical Sciences, supra, a standardreference text in this field.

[0692] Useful pharmaceutical dosage-forms for administration of thecompounds of this invention can be illustrated as follows:

[0693] Capsules

[0694] A capsule formulation of the present invention can be prepared byfilling standard two-piece hard gelatin capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6mg magnesium stearic.

[0695] Soft Gelatin Capsules

[0696] A soft gelatin capsule formulation of the present invention canbe prepared as follows. A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil can be prepared andinjected by means of a positive displacement pump into gelatin to formsoft gelatin capsules containing 100 mg of the active ingredient. Thecapsules should then be washed and dried.

[0697] Tablets

[0698] A tablet formulation of the present invention can be prepared byconventional procedures so that the dosage unit is 100 mg of activeingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 mg of microcrystalline cellulose, 11 mg ofstarch and 98.8 mg of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

[0699] Suspension

[0700] An aqueous suspension formulation can be prepared for oraladministration so that each 5 mL contain 25 mg of finely divided activeingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodiumbenzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

[0701] Injectable

[0702] A parenteral formulation suitable for administration by injectioncan be prepared by stirring 1.5% by weight of active ingredient in 10%by volume propylene glycol and water. The solution is sterilized bycommonly used techniques.

Combination Administration of Therapeutic Agents

[0703] The present invention provides a method for the treatment of HIVinfection which comprises administering, in combination, to a host inneed thereof a therapeutically effective amount of the following:

[0704] (a) a compound of formula (I); and

[0705] (b) at least one compound selected from the group consisting ofHIV reverse transcriptase inhibitors and HIV protease inhibitors, in oneor more sterile containers.

[0706] Each therapeutic agent component of this combination method(i.e., component (a) and (b) set forth above) can independently beadministered in any separate dosage form, such as those described above,and can be administered in various ways, as described above. In thefollowing description component (b) is to be understood to represent oneor more agents as described previously. Each individual therapeuticagent comprising component (b) may also be independently be administeredin any separate dosage form, such as those described above, and can beadministered in various ways, as described above.

[0707] Components (a) and any one or more of the agents comprisingcomponent (b) of the combination method of the present invention may beformulated together, in a single dosage unit (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.) as a combinationproduct. When component (a) and (b) are not formulated together in asingle dosage unit, the component (a) may be administered at the sametime as component (b) or in any order; for example component (a) of thisinvention may be administered first, followed by administration ofcomponent (b), or they may be administered in the revserse order. Ifcomponent (b) contains more that one agent, e.g., one RT inhibitor andone protease inhibitor, these agents may be administered together or inany order. When not administered at the same time, preferably theadministration of component (a) and (b) occurs less than about one hourapart. Preferably, the route of administration of component (a) and (b)is oral. The terms oral agent, oral inhibitor, oral compound, or thelike, as used herein, denote compounds which may be orally administered.Although it is preferable that component (a) and component (b) both beadministered by the same route (that is, for example, both orally) ordosage form, if desired, they may each be administered by differentroutes or dosage forms (for example, one component of the combinationmethod may be administered orally, and another component may beadministered intravenously).

[0708] As is appreciated by a medical practitioner skilled in the art,the dosage of the combination therapy of the invention may varydepending upon various factors such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration, the age, health and weight of the recipient, the natureand extent of the symptoms, the kind of concurrent treatment, thefrequency of treatment, and the effect desired, as described above.

[0709] The proper dosage of components (a) and (b) of the combinationmethod of this invention will be readily ascertainable by a medicalpractitioner skilled in the art, based upon the present disclosure. Byway of general guidance, typically a daily dosage may be about 100milligrams to about 1.5 grams of each component. If component (b)represents more than one compound, then typically a daily dosage may beabout 100 milligrams to about 1.5 grams of each agent of component (b).By way of general guidance, when the compounds of component (a) andcomponent (b) are administered in combination, the dosage amount of eachcomponent may be reduced by about 70-80% relative to the usual dosage ofthe component when it is administered alone as a single agent for thetreatment of HIV infection, in view of the synergistic effect of thecombination.

[0710] The combination products of this invention may be formulated suchthat, although the active ingredients are combined in a single dosageunit, the physical contact between the active ingredients is minimized.In order to minimize contact, for example, where the product is orallyadministered, one active ingredient may be enteric coated. By entericcoating one of the active ingredients, it is possible not only tominimize the contact between the combined active ingredients, but also,it is possible to control the release of one of these components in thegastrointestinal tract such that one of these components is notreleased. in the stomach but rather is released in the intestines.Another embodiment of this invention where oral administration isdesired provides for a combination product wherein one of the activeingredients is coated with a sustained-release material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low-viscosity grade ofhydroxypropyl methylcellulose or other appropriate materials as known inthe art, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component. In each formulation wherein contact is preventedbetween components (a) and (b) via a coating or some other material,contact may also be prevented between the individual agents of component(b).

[0711] Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

[0712] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time or concurrently by the same manner,. will bereadily apparent to those skilled in the art, based on the presentdisclosure.

[0713] Pharmaceutical kits useful for the treatment of HIV infection,which comprise a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of component (a) and one or morecompounds of component (b), in one or more sterile containers, are alsowithin the ambit of the present invention. Sterilization of thecontainer may be carried out using conventional sterilizationmethodology well known to those skilled in the art. Component (a) andcomponent (b) may be in the same sterile container or in separatesterile containers. The sterile containers of materials may compriseseparate containers, or one or more multi-part containers, as desired.Component (a) and component (b) may be separate, or physically combinedinto a single dosage form or unit as described above. Such kits mayfurther include, if desired, one or more of various conventionalpharmaceutical kit components, such as for example, one or morepharmaceutically acceptable carriers, additional vials for mixing thecomponents, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, may also be included in thekit.

[0714] As will be appreciated by one of skill in the art, numerousmodifications and variations of the present invention are possible inlight of the above teachings. It is therefore to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise than as specifically described herein.

What is claimed is:
 1. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or apharmaceutically acceptable salt form thereof, wherein: A is a ringselected from:

P is O or S; R^(b), at each occurrence, is independently selected fromH, F, Cl, Br, I, CN, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₁₋₄alkyl—O—, or C₁₋₄ alkyl—NH—, NH₂; R^(c), at each occurrence, isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, and C₁₋₄alkynyl; W is N or CR³; X is N or CR^(3a); Y is N or CR^(3b); Z is N orCR^(3c); provided that if two of W, X, Y, and Z are N, then theremaining are other than N; R¹ is selected from the group C₁₋₄ alkylsubstituted with 0-9 halogen, cyclopropyl, hydroxymethyl, and CN; R² isselected from the group methyl substituted with 0-3 R^(3f), C1-6 alkylsubstituted with 0-2 R⁴, C₂₋₆haloalkyl, C₂₋₅ alkenyl substituted with0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆ cycloalkylsubstituted with 0-2 R^(3d), phenyl substituted with 0-2 R^(3d), and 3-6membered heterocyclic system containing 1-3 heteroatoms selected fromthe group O, N, and S, substituted with 0-2 R^(3d); R³ is selected fromthe group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, CF₃, F, Cl, Br, I,—(CH₂) R⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —(CH₂)_(t)NHC(O)R⁷,—(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —S—C₁₋₄alkyl, —S(O)C₁₋₄alkyl,—S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ringcontaining 1-4 heteroatoms selected from the group O, N, and S; R^(3a)is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, CF₃,F, Cl, Br, I, —(CH₂)_(t)NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—(CH₂)_(t)NHC(O)R⁷, —(CH₂)_(t)NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —S—C₁₋₄alkyl,—S(O)C₁₋₄alkyl, —S(O)₂C₁₋₄alkyl, —SO₂NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S; alternatively, R³ and R³a together form —OCH₂O—; R^(3b) isselected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl,Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a),—NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3a) and R^(3b) togetherform —OCH₂O—; R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3b)and R^(3c) together form —OCH₂O—; R^(3d), at each occurrence, isindependently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy,OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3e), at eachoccurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH,C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3f), ateach occurrence, is independently selected from the group H, F, Cl, Br,I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, OCF₃, —O(CO)—R¹³, —OS(O)₂C₁₋₄alkyl,—NR¹³, —NHC(O)R¹³, —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —NHSO₂R¹⁰, and—SO₂NR¹²R^(12a); R⁴ is selected from the group H, F, Cl, Br, I, C₁₋₆alkyl substituted with 0-2 R^(3e), C₃₋₁₀ carbocycle substituted with 0-2R^(3e), phenyl substituted with 0-5 R^(3e), and a 5-10 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-2 R^(3e); R⁵ and R^(5a) areindependently selected from the group H and C₁₋₄ alkyl; alternatively,R⁵ and R^(5a), together with the nitrogen to which they are attached,combine to form a 5-6 membered ring containing 0-1 O or N atoms; R⁶ isselected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, and NR⁵R^(5a);R⁷ is selected from the group H, C₁₋₃ alkyl and C₁₋₃ alkoxy; R⁸ isselected from the group H, (C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy, (C₁₋₄alkoxy)carbonyl, C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀aryl)methylcarbonyl, (C₁₋₄ alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀arylcarbonyloxy(C₁₋₄ alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆alkyl)carbonyl; R⁹ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, (C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀aryloxy, (C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ arylcarbonyloxy(C₁₋₄alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl,phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆ alkyl) carbonyl; R¹⁰ isselected from the group C₁₋₄ alkyl and phenyl; R¹¹ is selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted with C₃₋₆cycloalkylsubstituted with 0-2 R^(3e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocyclesubstituted with 0-2 R^(3e); R¹² and R^(12a) are independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₆cycloalkylsubstituted with 0-2 R^(3e), and C₃₋₆ carbocycle substituted with 0-2R^(3e); alternatively, R¹² and R^(12a) can join to form 4-7 memberedheterocyclic ring; R¹³ is selected from the group H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —O—C₂₋₆ alkenyl,—O—C₂₋₆ alkynyl, NR¹²R^(12a), C₃₋₆carbocycle, and —O—C₃₋₆carbocycle; andt is selected from 0 and
 1. 2. A compound of claim 1 or pharmaceuticallyacceptable salt forms thereof, wherein: R² is selected from the groupmethyl substituted with 0-3 R^(3f), C₁₋₅ alkyl substituted with 0-2 R⁴,C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d), and phenyl substitutedwith 0-2 R^(3d), and 3-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-2R^(3d), wherein the heterocyclic system is selected from 2-pyridyl,3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R³ and R^(3a), at eachoccurrence, are independently selected from the group H, C₁₋₄ alkyl, OH,C₁₋₄ alkoxy, F, Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷,NHC(O)NR⁵R^(5a), and a 5-6 membered heteroaromatic ring containing 1-4heteroatoms selected from the group O, N, and S; alternatively, R³ andR^(3a) together form —OCH₂O—; R^(3b) and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₄ alkyl, OH, C₁₋₄ alkoxy, F,Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC (O)NR⁵R^(5a);alternatively, R^(3a) and R^(3b) together form —OCH₂O—; R⁴ is selectedfrom the group H, Cl, F, C₁₋₄ alkyl substituted with 0-2 R^(3e), C₃₋₆carbocycle substituted with 0-2 R^(3e), phenyl substituted with 0-5R^(3e), and a 5-6 membered heterocyclic system containing 1-3heteroatoms selected from the group O, N, and S, substituted with 0-2R^(3e); R⁵ and R^(5a) are independently selected from the group H, CH₃and C₂H₅; R⁶ is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅,and NR⁵R^(5a); and R⁷ is selected from the group CH₃, C₂H₅, CH(CH₃)₂,OCH₃, OC₂H₅, and OCH(CH₃)₂.
 3. A compound of claim 2, wherein: P is O;Ring A is:

R^(b), at each occurrence, is selected from H, F, Cl, and Br, C₁₋₄alkyl, CN, C₁₋₄ alkyl-NH-, NH₂; R^(c) is selected from H and methyl; Wis CR³; X is CR^(3a); Y is CR^(3b); Z is CR^(3c); R² is selected fromthe group methyl substituted with 0-3 R^(3f), C₁₋₃ alkyl substitutedwith 0-2 R⁴, C₂₋₃ alkenyl substituted with 0-2 R⁴, C₂₋₃ alkynylsubstituted with 0-1 R⁴, and C₃₋₆ cycloalkyl substituted with 0-2R^(3d); R³, R^(3a), R^(3b), and R^(3c), at each occurrence, areindependently selected from the group H, C₁₋₃ alkyl, OH, C₁₋₃ alkoxy, F,Cl, Br, I, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, and NHC(O) NR⁵R^(5a);alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3e), at eachoccurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH,C₁₋₄ alkoxy, OCF₃, F, Cl, —NR⁵R^(5a), —C(O)R⁶, and —SO₂NR⁵R^(5a);R^(3f), at each occurrence, is independently selected from the group H,F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —O(CO)—R¹³, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —NR¹²R^(12a); R⁴ is selected from the group H, Cl, F,C₁₋₄ alkyl substituted with 0-1 R^(3e), C₃₋₅ carbocycle substituted with0-2 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-1 R^(3e), wherein the heterocyclicsystem is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl,3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl,2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R⁵and R^(5a) are independently selected from the group H, CH₃ and C₂H₅; R⁶is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; R⁸ is H; R⁹ isH, methyl, ethyl, propyl, and i-propyl; R¹¹ is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocyclesubstituted with 0-2 R^(3e) wherein the C₃₋₆ carbocycle is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl; and R¹² andR^(12a) are independently selected from H, methyl, ethyl, propyl,i-propyl, butyl, i-butyl, t-butyl, and C₃₋₆ carbocycle substituted with0-2 R^(3e) wherein the C₃₋₆ carbocycle is selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and phenyl.
 4. A compound of claim3, or a pharmaceutically acceptable salt form thereof, wherein: R² isselected from the group methyl substituted with 0-3 R^(3f), C₁₋₃ alkylsubstituted with 1 R⁴, C₂₋₃ alkenyl substituted with 1 R⁴, and C₂₋₃alkynyl substituted with 1 R⁴; R³, R^(3a), R^(3b), and R^(3c), at eachoccurrence, are independently selected from the group H, C₁₋₃ alkyl, OH,C₁₋₃ alkoxy, F, Cl, NR⁵R^(5a), NO₂, —CN, C(O)R⁶, NHC(O)R⁷, andNHC(O)NR⁵R^(5a); alternatively, R³ and R^(3a) together form —OCH₂O—;R^(3e), at each occurrence, is independently selected from the groupCH₃, —OH, OCH₃, OCF₃, F, Cl, and —NR⁵R^(5a); R^(3f), at each occurrence,is independently selected from the group H, F, Cl, Br, I, C₁₋₄ alkyl,—OH, CN, —O—R¹¹, —O(CO)—R¹³, and —NR¹²R^(12a), —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —OS(O)₂methyl; R⁴ is selected from the group H, Cl, F,CH₃, CH₂CH₃, cyclopropyl substituted with 0-1 R^(3e),1-methyl-cyclopropyl substituted with 0-1 R^(3e), cyclobutyl substitutedwith 0-1 R^(3e), phenyl substituted with 0-2 R^(3e), and a 5-6 memberedheterocyclic system containing 1-3 heteroatoms selected from the groupO, N, and S, substituted with 0-1 R^(3e), wherein the heterocyclicsystem is selected from the group 2-pyridyl, 3-pyridyl, 4-pyridyl,2-imidazolyl, pyrazolyl, triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R⁵and R^(5a) are independently selected from the group H, CH₃ and C₂H₅; R⁶is selected from the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a);R⁷ is selected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; and R⁹ isselected from H and methyl.
 5. A compound of claim 4, or apharmaceutically acceptable salt form thereof, wherein: R² is selectedfrom the group methyl substituted with 0-2 R^(3f), methyl substitutedwith 0-2 R⁴, ethyl substituted with 0-2 R⁴, propyl substituted with 0-2R⁴, ethenyl substituted with 0-2 R⁴, 1-propenyl substituted with 0-2 R⁴,2-propenyl substituted with 0-2 R⁴, ethynyl substituted with 0-2 R⁴,1-propynyl substituted with 0-2 R⁴, 2-propynyl substituted with 0-2 R⁴,and cyclopropyl substituted with 0-1 R^(3d); R^(3e), at each occurrence,is independently selected from the group CH₃, —OH, OCH₃, OCF₃, F, Cl,and —NR⁵R^(5a); R⁴ is selected from the group H, Cl, F, CH₃, CH₂CH₃,cyclopropyl substituted with 0-1 R^(3e), 1-methyl-cyclopropylsubstituted with 0-1 R^(3e), cyclobutyl substituted with 0-1 R^(3e),phenyl substituted with 0-2 R^(3e), and a 5-6 membered heterocyclicsystem containing 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-1 R^(3e), wherein the heterocyclic system is selectedfrom the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R⁵ and R^(5a) areindependently selected from the group H, CH₃ and C₂H₅; R⁶ is selectedfrom the group H, OH, CH₃, C₂H₅, OCH₃, OC₂H₅, and NR⁵R^(5a); R⁷ isselected from the group CH₃, C₂H₅, OCH₃, and OC₂H₅; R⁸ is H.
 6. Acompound of claim 5, or a pharmaceutically acceptable salt form thereof,wherein: R¹ is selected from methyl, ethyl, propyl, i-propyl, butyl,cyclopropyl, CF₃, CF₂CH₃, CN, and hydroxymethyl; R² is selected from thegroup methyl substituted with 0-2 R^(3f), methyl substituted with 0-2R⁴, ethyl substituted with 0-2 R⁴, propyl substituted with 0-1 R⁴,ethenyl substituted with 0-2 R⁴, 1-propenyl substituted with 0-2 R⁴,2-propenyl substituted with 0-2 R⁴, ethynyl substituted with 0-2 R⁴,1-propynyl substituted with 0-2 R⁴; R³, R^(3b), and R^(3c) are H; R^(3e)is CH₃; R^(3f), at each occurrence, is independently selected from thegroup H, F, Cl, Br, I, C₁₋₄ alkyl, CN, —OH, —O—R¹¹, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, and —NR¹²R^(12a); R⁴ is selected from the group H,cyclopropyl substituted with 0-1 R^(3e), and a 5-6 membered heterocyclicsystem containing 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-1 R^(3e), wherein the heterocyclic system is selectedfrom the group 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazolyl,triazolyl, 1,3-dioxolanyl, and 1,3-dioxanyl; R¹² and R^(12a) areindependently selected from H, methyl, ethyl, propyl, and i-propyl, andC₃₋₆ carbocycle substituted with 0-2 R^(3e) wherein the C₃₋₆ carbocycleis selected from cyclopropyl.
 7. A compound of claim 6, or apharmaceutically acceptable salt form thereof, wherein the compound isof formula (Ic):


8. A compound of claim 1, or a pharmaceutically acceptable salt formthereof, wherein the compound of formula (I) is selected from:7-fluoro-2-methyl-5-[(6-methyl-2-pyridinyl)methyl]-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H) -one;5-(2-cyclopropylethynyl)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-propyl-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-butyl-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one; 7-fluoro-5-(4-fluorophenylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(2-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(isopropyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(3-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(4-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(3-propynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(2-pyridylethynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(2-(2-pyridyl)ethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;3-chloro-7-fluoro-5-propyl-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(3-propenyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-cyclopropylethyl)-7-fluoro-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(ethynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-fluoro-5-(2-ethoxyethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-Butyl-7-chloro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(2-cyclopropylethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-cyclopropylethynyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(N-cyclopropylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one; 7-Chloro-5-hydroxymethy1-5-trifluoromethyl-5,10-dihydrobenzo [b]-1,7-naphthyridin-1(2H)-one;7-Chloro-3-methyl-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(2-cyclopropylethyl)-3-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(2-methoxyethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(N-methyl-N-i-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(cyclopropylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-propylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(cyclobutylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-butylaminomethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Cyano-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Cyano-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(cyclopropylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(cyclopropanesulfinylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(t-butylsulfinylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(methylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(ethylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-propylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Fluoro-5-(i-propylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(t-butylsulfanylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(cyclopropylmethoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(cyclobutoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(Cyclobutoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(Cyclopropylmethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-3-methyl-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-3-methyl-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Cyano-3-methyl-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-2-methyl-5-(i-propoxymethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;3,7-Dichloro-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;4,7-Dichloro-5-(n-butyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(ethoxyethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-butyl)-5-methyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-propoxymethyl)-5-methyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-butyl)-5-cyano-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-butyl)-5-(hydroxymethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-butyl)-5-difluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(i-propoxymethyl)-5-difluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(n-Butyl)-5-(1,1-difluoroethyl)-7-Fluoro-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(n-butyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Cyano-5-(n-butyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;7-Chloro-5-(ethoxymethyl)-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(allyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-methyl-1-propenyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(1-propynyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(cyanomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(ethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(dimethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(methylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-ethoxyethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(i-propylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(diethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(cyclopropylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(pentyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-butyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(vinyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(imidazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(pyrazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(1,2,4-triazolylethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-propylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-propoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(methylethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(i-propylethylamino)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(pyrrolidinyl)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(methoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-propoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(3-pentanylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(dimethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(cyclopropylmethylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(allylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-((R)-sec-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-((S)-sec-butylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(diethoxymethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;3-chloro-5-(propyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(butyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(i-propoxy)ethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-propylaminomethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(i-propoxymethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-ethoxyethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(sec-butylaminomethyl)-7-fluoro-2-methyl-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H) -one;5-(cyclopentylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(cyclobutylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(dimethylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(pyrrolidinylmethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(cyclopropylaminomethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(dimethoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(diethoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;5-(2-(1,3-dioxolanyl)methyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one; and5-(2-(methoxy)ethyl)-7-fluoro-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one.
 9. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound according to one of claim orpharmaceutically acceptable salt form thereof.
 10. A method for treatingHIV infection which comprises administering to a host in need of suchtreatment a therapeutically effective amount of a compound according toone of claim 1 or pharmaceutically acceptable salt form thereof.
 11. Amethod of treating HIV infection which comprises administering, incombination, to a host in need thereof a therapeutically effectiveamount of: (a) a compound according to one of claim 1; and, (b) at leastone compound selected from the group consisting of HIV reversetranscriptase inhibitors, HIV protease inhibitors, fusion inhibitors,and CCR-5 inhibitors.
 12. A method of claim 11, wherein the reversetranscriptase inhibitor is selected from the group AZT, ddC, ddI, d4T,3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442,HBY 097, HBY1293, GW867, ACT, UC-781, UC-782, RD4-2025, MEN 10979 AG1549(S1153), TMC-120, TMC-125, Calanolide A, and PMPA, and the proteaseinhibitor is selected from the group saquinavir, ritonavir, indinavir,amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272,LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392,U-140690, ABT-378, DMP-450, AG-1776, VX-175, MK-944, and VX-478, theCCR-5 inhibitor is selected from TAK-779 (Takeda), SC-351125 (SCH-C,Schering) and SCH-D (Schering), and the fusion inhibitor is selectedfrom T-20 and T1249.
 13. A method of claim 12, wherein the reversetranscriptase inhibitor is selected from the group AZT, efavirenz, and3TC and the protease inhibitor is selected from the group saquinavir,ritonavir, nelfinavir, and indinavir.
 14. A method of claim 13, whereinthe reverse transcriptase inhibitor is AZT.
 15. A method of claim 13,wherein the protease inhibitor is indinavir.
 16. A pharmaceutical kituseful for the treatment of HIV infection, which comprises atherapeutically effective amount of: (a) a compound according to one ofclaim 1; and, (b) at least one compound selected from the groupconsisting of HIV reverse transcriptase inhibitors and HIV proteaseinhibitors, in one or more sterile containers.
 17. A compound accordingto one of claim 1 for use in therapy.
 18. The use of a compoundaccording to one of claim 1 for the manufacture of a medicament for thetreatment of HIV infection.
 19. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or apharmaceutically acceptable salt form thereof, wherein: A is a ringselected from:

P is O or S; R^(b) is H, F, Cl, Br, I, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, C₁₋₄ alkyl—O—, or C₁₋₄ alkyl—NH—; W is N or CR³; X is N orCR^(3a); Y is N or CR^(3b); Z is N or CR^(3c); provided that if two ofW, X, Y, and Z are N, then the remaining are other than N; R¹ isselected from the group C₁₋₃ alkyl substituted with 0-7 halogen andcyclopropyl; R² is selected from the group —R^(2c), —OR^(2c),—OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —O(CH₂)₂CHR^(2a)R^(2b),OCHR^(2a)C (R^(2a))═C(R^(2b))₂, —OCHR^(2a)C(R^(2a))═C(R^(2b))₂,—OCHR^(2a)C═C-R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b),—S(CH₂)₂CHR^(2a)R^(2b), —SCHR^(2a)C (R^(2a))═C (R^(2b))₂,—SCHR^(2a)C(R^(2a))═(R^(2b))₂, SCHR^(2a)C≡C-R^(2b), NR^(2a)R^(2c),—NHCHR^(2a)R^(2b), —NHCH₂CHR^(2a)R^(2b), —NH(CH₂)₂CHR^(2a)R^(2b),—NHCHR^(2a)C(R^(2a))═C(R^(2b))₂, —NHCHR^(2a)C(R^(2a))═(R^(2b))₂, and—NHCHR^(2a)C≡C-R^(2b); R^(2a) is selected from the group H, CH₃, CH₂CH₃,CH(CH₃)₂, and CH₂CH₂CH₃; R^(2b) is H or R^(2c); R^(2c) is selected fromthe group methyl substituted with 0-3 R^(3f), C₁₋₆ alkyl substitutedwith 0-2 R⁴, C₂₋₅ alkenyl substituted with 0-2 R⁴, C₂₋₅ alkynylsubstituted with 0-1 R⁴, C₃₋₆ cycloalkyl substituted with 0-2 R^(3d),phenyl substituted with 0-2 R^(3d), and 3-6 membered heterocyclic systemcontaining 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-2 R^(3d); alternatively, the group —NR^(2a)R^(2c)represents a 4-7 membered cyclic amine, wherein 0-1 carbon atoms arereplaced by O or NR⁵; R³ is selected from the group H, C₁₋₄ alkyl, —OH,C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—NHC(O)R⁷ —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S; R^(3a) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, —SO₂NR⁵R⁵a, and a 5-6 memberedheteroaromatic ring containing 1-4 heteroatoms selected from the groupO, N, and S; alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3b)is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl,Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a),—NHSO₂R¹¹, and —SO₂NR⁵R^(5a); alternatively, R^(3a) and R^(3b) togetherform —OCH₂O—; R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3b)and R^(3c) together form —OCH₂O—; R^(3d), at each occurrence, isindependently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy,OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3e), at eachoccurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH,C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3f), ateach occurrence, is independently selected from the group H, F, Cl, Br,I, C₁₋₄ alkyl, —OH, —O—R¹¹, —O—C₃₋₁₀ carbocycle substituted with 0-2R^(3e), OCF₃, —O(CO)-R¹³, —OS(O)₂C₁₋₄alkyl, —NR¹²R^(12a), —C(O)R¹³,—NHC(O)R¹³, —NHSO₂R¹⁰, and —SO₂NR¹²R^(12a); R⁴ is selected from thegroup H, F, Cl, Br, I, C₁-₆ alkyl substituted with 0-2 R^(3e), C₃₋₁₀carbocycle substituted with 0-2 R³e, phenyl substituted with 0-5 R^(3e),and a 5-10 membered heterocyclic system containing 1-3 heteroatomsselected from the group O, N, and S, substituted with 0-2 R^(3e); R⁵ andR^(5a) are independently selected from the group H and C₁₋₄ alkyl;alternatively, R⁵ and R^(5a), together with the nitrogen to which theyare attached, combine to form a 5-6 membered ring containing 0-1 O or Natoms; R⁶ is selected from the group H, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, andNR⁵R^(5a); R⁷ is selected from the group H, C₁₋₃ alkyl and C₁₋₃ alkoxy;R⁸ is selected from the group H, (C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy,(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy, (C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀aryl)methylcarbonyl, (C₁₋₄ alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀arylcarbonyloxy(C₁₋₄ alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl,phenylaminocarbonyl, phenyl(C₁₋₄ alkoxy) carbonyl, and NR⁵R^(5a)(C₁₋₆alkyl) carbonyl; R⁹ is selected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, andC₁₋₄ alkynyl; R¹⁰ is selected from the group C₁₋₄ alkyl and phenyl; R¹¹is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted withC₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ carbocycle substitutedwith 0-2 R^(3e); R¹² and R^(12a) are independently selected from H, C₁₋₆alkyl, and C₃₋₆ carbocycle substituted with 0-2 R^(3e); alternatively,R¹² and R^(12a) can join to form 4-7 membered ring; and R¹³ is selectedfrom the group H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, -O-C₂₋₆ alkenyl, —O—C₂₋₆ alkynyl, NR¹²R^(12a), C₃₋₆carbocycle, and —O—C₃₋₆carbocycle.
 20. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or apharmaceutically acceptable salt form thereof, wherein: A is a ringselected from:

P is O or S; R^(b) is H, F, Cl, Br, I, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, C₁₋₄ alkyl—O—, or C₁₋₄ alkyl—NH—; W is N or CR³; X is N orCR^(3a); Y is N or CR^(3b); Z is N or CR^(3c); provided that if two ofW, X, Y, and Z are N, then the remaining are other than N; R¹ isselected from the group C₁₋₃ alkyl substituted with 0-7 halogen andcyclopropyl; R² is selected from the group —R^(2c), —OR^(2c),—OCHR^(2a)R^(2b), —OCH₂CHR^(2a)R^(2b), —O(CH₂)₂CHR^(2a)R^(2b),OCHR^(2a)C(R^(2a))═C(R^(2b))₂, OCHR^(2a)C(R^(2a))═C(R^(2b))₂,—OCHR^(2a)C≡C—R^(2b), —SR^(2c), —SCHR^(2a)R^(2b), —SCH₂CHR^(2a)R^(2b),—S(CH₂)₂CHR^(2a)R^(2b), —SCHR^(2a)C(R^(2a))═C(R^(2b))₂,—SCHR^(2a)C(R^(2a))═(R^(2b))₂, —SCHR^(2a)C≡C—R^(2b), —NR^(2a)R^(2c),—NHCHR^(2a)R^(2b), —NHCH₂CHR^(2a)R^(2b), —NH(CH₂)₂CHR^(2a)R^(2b),—NHCHR^(2a)C(R^(2a))═C(R^(2b))₂, —NHCHR^(2a)C(R^(2a))═(R^(2b))₂, and—NHCHR^(2a)C4 C—R^(2b); R^(2a) is selected from the group H, CH₃,CH₂CH₃, CH(CH₃)₂, and CH₂CH₂CH₃; R^(2b) is H or R^(2c); R^(2c) isselected from the group C₁₋₆ alkyl substituted with 0-2 R⁴, C₂₋₅ alkenylsubstituted with 0-2 R⁴, C₂₋₅ alkynyl substituted with 0-1 R⁴, C₃₋₆cycloalkyl substituted with 0-2 R^(3d), phenyl substituted with 0-2R^(3d), and 3-6 membered heterocyclic system containing 1-3 heteroatomsselected from the group O, N, and S, substituted with 0-2 R^(3d);alternatively, the group -NR^(2a)R^(2c) represents a 4-7 membered cyclicamine, wherein 0-1 carbon atoms are replaced by O or NR⁵; R³ is selectedfrom the group H, C₁₋₄ alkyl, -OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I,—NR⁵R^(5a), —NO₂, —CN, —C (O) R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a),—NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ringcontaining 1-4 heteroatoms selected from the group O, N, and S; R^(3a)is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl,Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷, —NHC(O)NR⁵R^(5a),—NHSO₂R¹⁰, —SO₂NR⁵R^(5a), and a 5-6 membered heteroaromatic ringcontaining 1-4 heteroatoms selected from the group O, N, and S;alternatively, R³ and R^(3a) together form —OCH₂O—; R^(3b) is selectedfrom the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I,—NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O) R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰,and —SO₂NR⁵R^(5a); alternatively, R^(3a) and R^(3b) together form—OCH₂O—; R^(3c) is selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄alkoxy, OCF₃, F, C1, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); alternatively, R^(3b)and R^(3c) together form —OCH₂O—; R^(3d), at each occurrence, isindependently selected from the group H, C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy,OCF₃, F, Cl, Br, I, —NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶, —NHC—(O)R⁷,—NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R^(3e), at eachoccurrence, is independently selected from the group H, C₁₋₄ alkyl, —OH,C₁₋₄ alkoxy, OCF₃, F, Cl, Br, I, NR⁵R^(5a), —NO₂, —CN, —C(O)R⁶,—NHC(O)R⁷, —NHC(O)NR⁵R^(5a), —NHSO₂R¹⁰, and —SO₂NR⁵R^(5a); R⁴ isselected from the group H, R^(3d)F, Cl, Br, I, C₁₋₆ alkyl substitutedwith 0-2 R^(3e), C₃₋₁₀ carbocycle substituted with 0-2 R^(3e), phenylsubstituted with 0-5 R^(3e), and a 5-10 membered heterocyclic systemcontaining 1-3 heteroatoms selected from the group O, N, and S,substituted with 0-2 R^(3e); R⁵ and R^(5a) are independently selectedfrom the group H and C₁₋₄ alkyl; alternatively, R⁵ and R^(5a), togetherwith the nitrogen to which they are attached, combine to form a 5-6membered ring containing 0-1 O or N atoms; R⁶ is selected from the groupH, OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, and NR⁵R^(5a); R⁷ is selected from thegroup H, C₁₋₃ alkyl and C₁₋₃ alkoxy; R⁸ is selected from the group H,(C₁₋₆ alkyl)carbonyl, C₁₋₆ alkoxy, (C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ aryloxy,(C₆₋₁₀ aryl)oxycarbonyl, (C₆₋₁₀ aryl)methylcarbonyl, (C₁₋₄alkyl)carbonyloxy(C₁₋₄ alkoxy)carbonyl, C₆₋₁₀ arylcarbonyloxy(C₁₋₄alkoxy)carbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl,phenyl(C₁₋₄ alkoxy)carbonyl, and NR⁵R^(5a)(C₁₋₆ alkyl) carbonyl; R⁹ isselected from H, C₁₋₄ alkyl, C₁₋₄ alkenyl, and C₁₋₄ alkynyl; and R¹⁰ isselected from the group C₁₋₄ alkyl and phenyl.